Osimertinibe comparado a Erlotinibe Gefitinibe ou quimioterapia para tratamento de carcinoma pulmonar de células não pequenas com mutação do gene do receptor do fator de crescimento epidérmico (EFGR): revisão rápida / Osimertinib compared to erlotinib, gefitinib or chemotherapy for the treatment of non-small cell pumonary carcinoma with epidermal growth factor receptor (EFGR) gene mutation: rapid review

Mesilato de osimertinibe, gefitinibe, erlotinibe, quimioterapia padrão. Indicação: Câncer de pulmão de células não pequenas com mutação do receptor do fator de crescimento epidérmico (EGFR). Pergunta: Mesilato de osimertinibe é mais eficaz e seguro que gefitinibe, erlotinibe ou quimioterapia para os desfechos de sobrevida global, sobrevida livre de progressão e de segurança no tratamento de carcinoma pulmonar de células não pequenas com mutação do EGFR? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED e EPISTEMONIKOS, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Resultados: Foram selecionadas duas revisões sistemáticas que atenderam aos critérios de elegibilidade. Conclusão: Mesilato de osimertinibe é mais eficaz do que gefitinibe ou erlotinibe na melhora da sobrevida global e da sobrevida livre de progressão em pacientes virgens de tratamento. Em pacientes previamente tratados, o mesilato de osimertinibe não é superior à quimioterapia padrão à base de platina no prolongamento da sobrevida global, mas é mais eficaz no aumento da sobrevida livre de progressão. Para câncer avançado, mesilato de osimertinibe não é mais eficaz do que a quimioterapia com ou sem pemetrexede para prolongar a sobrevida global, mas é mais eficaz em melhorar a sobrevida livre de progressão. Gefitinibe combinado com quimioterapia à base de pemetrexede foi superior à quimioterapia com ou sem pemetrexede na melhora da sobrevida global e da sobrevida livre de progressão

Osimertinib mesylate, gefitinib, erlotinib, standard chemotherapy. Indication: Non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. Question: Is osimertinib mesylate more effective and safer than gefitinib, erlotinib or chemotherapy for overall survival, progression-free survival and safety outcomes in the treatment of non-small cell lung cancer with EGFR mutation? Methods: A bibliographic search was done in the PUBMED and EPISTEMONIKOS database, following predefined search strategies. The methodological quality of systematic reviews was evaluated using the Assessing the Methodological Quality of Systematic Reviews Version 2 tool. Results: Two systematic reviews were selected because they met the eligibility criteria. Conclusion: Osimertinib mesylate is more effective than gefitinib or erlotinib in improving overall survival and progression-free survival in treatment-naive patients. In previously treated patients, osimertinib mesylate is not superior to standard platinum-based chemotherapy in prolonging overall survival, but it is more effective in increasing progression-free survival. For advanced cancer, osimertinib mesylate is not more effective than chemotherapy with or without pemetrexed in prolonging overall survival, but it is more effective in improving progression-free survival. Gefitinib combined with pemetrexed-based chemotherapy was superior to chemotherapy with or without pemetrexed in improving overall survival and progression-free survival

Effect of Reduning Injection， Shenfu Injection Combined with Gefitinib on Proliferation， Stemness Characteristics and Metabolism of Non-small Cell Lung Cancer Cells / 中国实验方剂学杂志

ObjectiveTo compare and observe the effect of Reduning injection （mainly clearing heat）， Shenfu injection （mainly warming Yang） combined with gefitinib on the proliferation， apoptosis， stemness characteristics and metabolism of lung cancer cells. MethodDifferent non-small cell lung cancer （NSCLC） cell lines were selected and intervened with gefitinib （5， 10， 20 μmol·L-1）， Reduning injection （0.6%， 0.9%）， Shenfu injection （0.6%， 0.9%）， gefitinib combined with Reduning injection， and gefitinib combined with Shenfu injection. Cell proliferation in each group was detected by cell counting kit-8 （CCK-8） assay， and cell apoptosis was detected by flow cytometry. The mRNA and protein expressions of lung cancer stem cell markers sex determining region Y-box 2 （Sox2） and aldehyde dehydrogenase family 1 member A1 （ALDH1A1） were determind by real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. The redox ratio of lung cancer cells was observed by femtosecond label-free imaging （FLI） and energy metabolism instrument was used to determine the glycolysis level in cells. ResultCompared with the blank group， Reduning injection reduced the survival rate of lung cancer cells （P<0.05）， increased the apoptosis rate （P<0.05）， down-regulated the mRNA and protein expressions of Sox2 and ALDH1A1 （P<0.05）， and up-regulated the redox ratio of cells （P<0.05）， while Shenfu injection exerted no remarkable effect on the above indexes. In addition， compared with gefitinib alone， Reduning injection combined with gefitinib inhibited the survival rate of lung cancer cells （P<0.05）， promoted the cell apoptosis （P<0.05）， down-regulated the mRNA and protein expressions of Sox2 and ALDH1A1 （P<0.05）， up-regulated the redox ratio of cells （P<0.05）， and lowered the proton efflux rate of glycolysis （P<0.05）， while Shenfu injection combined with gefitinib failed to affect these indexes of lung cancer cells significantly. ConclusionReduning injection may inhibit stemness characteristics of tumor cells by regulating their metabolism to enhance the proliferation-inhibiting and pro-apoptotic effects of gefitinib on lung cancer cells， while Shenfu injection had no significant enhancing effect on gefitinib. This indicates that epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKIs） should be used in combination with heat-clearing Chinese medicines.

Clinical observation of icotinib versus gefitinib in the treatment of EGFR-mutated advanced non-small cell lung cancer / 中国药房

OBJECTIVE To compare the efficacy and safety of icotinib and gefitinib in the treatment of epidermal growth factor receptor （EGFR）-mutated advanced non-small cell lung cancer （NSCLC）. METHODS The data of 146 patients with EGFR- mutant advanced NSCLC of our Hospital from December 2015 to September 2021 were retrospectively analyzed and divided into the gefitinib group （73 cases） and the icotinib group （73 cases） according to the drug use. Patients in the gefitinib group were given 0.25 g of gefitinib tablets once a day orally by single drug or combined with conventional chemotherapy， while patients in the icotinib group were given 125 mg of icotinib hydrochloride tablets three times a day orally by single drug or combined with conventional chemotherapy. Short-term efficacy， progression-free survival （PFS） were observed； Cox regression model was used to analyze the factors affecting the prognosis of patients； the occurrence of ADR were observed in the two groups. RESULTS There was no statistically significant difference in the objective remission rate， disease control rate， and the incidence of grade 1-2 and grade 3-4 adverse drug reactions between the two groups （P＞0.05）； median PFS was significantly better in the icotinib group than in the gefitinib group （P＝0.048）. Results of subgroup analysis based on patients basic information showed that compared with the gefitinib group， PFS of female [HR＝0.57，95%CI（0.34，0.96），P＝0.031] and non-brain metastatic patients [HR＝0.58，95%CI（0.36，0.91），P＝0.017] in icotinib group were prolonged significantly. Results of regression model analysis showed that EGFR19 exon Del mutation [HR＝0.50， 95%CI（0.25，1.00）， P＝0.049]， EGFR21 exon L858R mutation [HR＝0.44， 95%CI（0.21，0.89）， P＝0.022] and icotinib treatment [HR＝0.65， 95%CI （0.44，0.96）， P＝0.030] were influential factors for prognosis. CONCLUSIONS The short-term efficacy and safety of icotinib and gefitinib in the treatment of EGFR- mutant advanced NSCLC are comparable， but icotinib can significantly prolong the patients’ PFS； EGFR19 exon Del， EGFR21 exon L858R mutations and icotinib treatment are factors affecting patients’ prognosis.

Analysis of the synergistic effect of triptolide combined with gefitinib on EGFR-mutant NSCLC cells / 中国药房

OBJECTIVE To investigate the synergistic effect of triptolide （TPL） combined with epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） gefitinib on EGFR-mutated non-small cell lung cancer （NSCLC） cells and its potential mechanism. METHODS Human NSCLC cell lines H1975 （EGFR T790M/L858R mutated drug-resistant cell lines） and H1299 （EGFR wild-type non-drug-resistant cell lines） were cultured in vitro. MTT method was used to detect cell activity， and the effect of combined medication was evaluated by the combination index （CI）. The H1975 cells were divided into blank group， low- concentration and high-concentration groups of TPL （5 nmol/L or 15 nmol/L）， gefitinib group （2 μmol/L）， low-concentration and high-concentration groups of TPL+gefitinib （5 nmol/L TPL+2 μmol/L gefitinib， 15 nmol/L TPL+2 μmol/L gefitinib）. Flow cytometry was used to detect the apoptosis of H1975 cells and the distribution of the cell cycle. Molecular docking studies were used to predict the binding ability of TPL to EGFR. The expressions of phosphatidylinositol 3 kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR） pathway and autophagy-related proteins [microtubule-associated protein 1 light chain 3α （MAP1LC3A）， MAP1LC3B] in H1975 cells were detected by flow cytometry. RESULTS TPL had a strong inhibitory effect on the proliferation of H1975 and H1299 cells in a time-dependent and dose-dependent manner. Forty-eight hours treatment of 5 or 15 nmol/L TPL combined with gefitinib had a synergistic inhibitory effect on the proliferation of H1975 cells （CI＜1）， while there was no synergistic inhibitory effect on H1299 cells （CI＞1）. Compared with the blank group， the apoptosis rate and the proportion of H1975 cells at G0/G1 phase were increased significantly in administration groups， while the proportions of cells at S phase and G2/M phase （except for several TPL groups） were decreased significantly， and the combination group had better effects （P＜0.05）. Molecular docking studies showed that the hydroxyl radical of TPL could form hydrogen bonds with the Thr854 residue of the product encoded by EGFR T790M/L858R mutation. Compared with the blank group， the expressions of pathway-related proteins were down-regulated significantly in administration groups， while those of autophagy-related proteins were up-regulated significantly， and the combination group had better effects （P＜0.05）. CONCLUSIONS TPL combined with gefitinib can synergically inhibit the proliferation activity of EGFR-mutated NSCLC cells， the mechanism of which may be related to the down-regulation of PI3K/Akt/ mTOR pathway and induction of autophagy.

Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells via ROS/Sirt3/SOD2 Pathway / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.@*METHODS@#PC-9 and A549 cells were cultured in vitro and treated with 1 µmol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 µmol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.@*RESULTS@#CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).@*CONCLUSIONS@#The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.

Comparison of gefitinib plus chemotherapy versus gefitinib alone for advanced non-small-cell lung cancer: A meta analysis

Abstract This study aimed to perform a meta-analysis comparing the efficacy and safety of gefitinib in combination with chemotherapy versus gefitinib alone in patients with advanced Non-Small Cell Lung Cancer (NSCLC). We searched databases for clinical studies that reported the efficacy or safety of gefitinib plus chemotherapy in comparison with gefitinib alone. Raw data from included studies were extracted and pooled to calculate the Odds Ratio (OR) for Objective Response Rate (ORR) and Disease Control Rate (DCR), the Hazard Ratio (HR) for Progression-Free Survival (PFS) and Overall Survival (OS), and OR for complication ≥ Grade 3. A total of 10 studies containing 1,528 patients with NSCLC were identified and included in the analysis. Gefitinib plus chemotherapy showed significantly better efficacy in improving ORR (OR = 1.54; 95% CI [Confidence Interval], 1.13‒2.1; p = 0.006), DCR (OR = 1.62; 95% CI 1.14‒2.29; p = 0.007), PFS (HR=1.67; 95% CI 1.45‒1.94; p < 0.001) and OS (HR = 1.49; 95% CI 1.2‒1.87; p < 0.001) as compared with gefitinib alone. Consistent results were observed in the sub-population with positive EGFR mutation. The combination of gefitinib with chemotherapy had a significantly higher risk of complication (≥ Grade 3) with an OR of 3.29 (95% CI 2.57‒4.21; p < 0.001). The findings in the present study suggest that the combination of gefitinib with chemotherapy can provide better disease response and survival outcomes for patients with advanced NSCLC.

A study on treatment of locally advanced squamous cell carcinoma of head and neck with radiation along with cisplatin or gefitinib

Background: Cisplatin based Concurrent chemo-radiation (CTRT) is the corner stone for treatment of locally advanced head and neck carcinoma. Epidermal growth factor receptor(EGFR) expression by squamous cell carcinoma which is associated with cancer development and progression,leads to emergence of anti-EGFR agents as a therapeutic option. In this study we compare cisplatin based CTRT against gefitinib based CTRT in terms of disease control and acute toxicity profile. Material and Methods: Stage III and IV squamous cell carcinoma of Head and neck region (excluding nasopharynx) were randomised into two groups. Control group received conventionally fractionated radiotherapy of 66Gy in 33fractions, over six and half weeks with concurrent weekly cisplatin. Study group received same dose of radiation with concurrent daily oral Gefitinib. All patients were followed up weekly during the treatment and then 6-8 weeks after completion of treatment and thereafter 3 monthly. Results: Overall response rate (complete response + partial response) was comparable for both arms (75% vs 76.2%, p value-0.881). Radiation with cisplatin was associated with significantly higher skin (28.6% vs 15%,p value-0.037) and mucosal (23.8% vs 5%,p-value-0.047) toxicities. Gefitinib containing arm showed significantly higher grade 3 diarrhoea (10% vs 0%, p-value-0.01) and skin rash (6% vs 0%, p -value-<0.001).With a median follow-up of 12.5 months Disease free survival (DFS) was not significantly different between the arms(12 vs 13 months). Conclusion: Gefitinib based CTRT is non-inferior to cisplatin based CTRT for the treatment of locally advanced head and neck carcinoma with acceptable toxicity profile.

Mutations of epidermal growth factor receptor gene in non-small cell lung cancer patients and the correlation with clinical characteristics and therapeutic effects / 肿瘤研究与临床

Objective:To investigate the clinical characteristics of non-small cell lung cancer (NSCLC) patients with different epidermal growth factor receptor (EGFR) gene mutations and the comparison of therapeutic effects.Methods:The clinical data of 324 patients with NSCLC admitted to the 904th Hospital of the Joint Service Support Force of PLA from April 2018 to June 2020 were retrospectively analyzed. Gene sequencing method was used to detect EGFR gene and mutations of exons 19 and 21. NSCLC patients with EGFR gene mutations were divided into group A (mutation of exon 19 of EGFR gene) and group B (mutation of exon 21 of EGFR gene). Both groups were treated with gefitinib combined with TP (paclitaxel + cisplatin) regimen for 3 months. The clinical features, efficacy and adverse reactions of the two groups were compared.Results:Among 234 NSCLC patients, 107 cases (45.73%) had EGFR gene mutations. Among them, there were 49 cases in group A (including delE746-A750 mutation in 32 cases, delL747-P753insS 3 mutation in 8 cases, delL747-A750 1 mutation in 6 cases, delL747-T751 1 mutation in 3 cases), and there were 58 cases in group B (all L858R mutations), and no double mutations in exons 19 and 21 were found in both groups. There were no significant differences in gender, TNM staging, pathological type, smoking history, age, degree of differentiation, tumor location, tumor diameter, and lymph node metastasis in the two groups (all P > 0.05). The difference in the clinical control rates of group A and group B was not statistically significant [91.8% (45/49) vs. 89.7% (52/58), χ2=0.15, P = 0.699]. The incidence of grade Ⅲ-Ⅳ adverse reactions in the two groups during treatment had no statistically significant differences (all P > 0.05). Conclusions:EGFR mutation rate in NSCLC patients is relatively high, most of which are EGFR exons 19 and 21 mutations. Gefitinib combined with TP regimen in the treatment of EGFR exons 19 and 21 mutations in NSCLC patients has good curative effects and high safety.

Establishment of an efficacy prediction model for gefitinib in non-small cell lung cancer patients based on ABCB1 and ABCG2 gene polymorphisms / 国际肿瘤学杂志

Objective:To explore the relationship between ABCB1 or ABCG2 gene polymorphisms and therapeutic effects of gefitinib in non-small cell lung cancer (NSCLC) patients, and establish a prediction model of efficacy.Methods:A total of 176 NSCLC patients with epidermal growth factor receptor (EGFR) -sensitive mutation treated with gefitinib admitted to Department of Pulmonary Disease of Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine of Hebei Province from December 2018 to December 2020 were employed as subjects, and all patients were detected ABCB1 and ABCG2 gene polymorphisms. Patients were divided into remission group and non-remission group according to curative effect after 3 months of gefitinib treatment. The clinical data, ABCB1 and ABCG2 gene polymorphisms, levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125) were compared between the two groups. The related factors of failure to remission after treatment were analyzed by multivariate logistic regression analysis. Combined with ABCB1 and ABCG2 gene polymorphisms, the prediction model for gefitinib efficacy was constructed and the nomogram was drawn.Results:During the follow-up period, 5 patients were lost to follow-up and 7 patients withdrew from the trial due to intolerable adverse effects, finally 108 patients were employed as remission group, and 56 patients were employed as non-remission group. The numbers of GG, GT and TT at ABCB1 rs2032582 in the remission group were 49, 50 and 9, and those in the non-remission group were 12, 35 and 9, with a statistically significant difference ( χ2=9.56, P=0.008). The numbers of GG, GA and AA at ABCG2 rs2231137 in the remission group were 13, 72 and 23, and those in the non-remission group were 11, 42 and 3, with a statistically significant difference ( χ2=7.74, P=0.021). Before treatment, the levels of serum CEA in the remission group and the non-remission group were (34.28±5.11) ng/ml and (37.88±7.05) ng/ml, with a statistically significant difference ( t=3.74, P<0.001). The levels of CA125 of the two groups were (27.24±6.50) U/ml and (33.31±6.09) U/ml, with a statistically significant difference ( t=-5.79, P<0.001). Multivariate logistic regression analysis showed that TT at rs2032582 of ABCB1 gene ( OR=12.99, 95% CI: 3.17-53.23, P<0.001), GG at rs2231137 of ABCG2 gene ( OR=7.75, 95% CI: 1.36-44.07, P=0.021) and GA ( OR=6.94, 95% CI: 1.47-32.84, P=0.015), CA125 ( OR=1.18, 95% CI: 1.10-1.28, P<0.001) were independent risk factors of failure to remission in NSCLC patients with EGFR sensitive mutation after treatment. The consistency index (C-index) of nomogram for predicting failure to remission was 0.92 (95% CI: 0.86-0.94) . Conclusion:ABCB1 rs2032582 and ABCG2 rs2231137 polymorphisms are related to therapeutic effects of gefitinib in the NSCLC patients, the nomogram based on the two genes combined with serum CA125 can predict efficacy of gefitinib.

FOXC1 Knockdown Reverses Gefitinib Resistance in Non-small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#Lung cancer is the malignant tumor with the highest incidence and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for about 80%. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapy has been playing an important role in treatment of NSCLC. However, unavoidable therapeutic resistance significantly limits the clinical efficacy of EGFR-TKI. As a key member of the forkhead box protein family, FOXC1 is aberrantly expressed in NSCLC and involved in NSCLC progression. The aim of this work is to investigate the effect and potential mechanism of FOXC1 on gefitinib resistance in NSCLC.@*METHODS@#Western blot was performed to assess the expression of FOXC1 protein in HCC827/GR cells. Immunohistochemistry (IHC) assays were performed in human NSCLC tissues with gefitinib resistance. HCC827/GR cells were transfected with shRNA specifically targeting FOXC1 mRNA and stable cell lines were established. The effects of FOXC1 on cell viability and apoptosis were analyzed using a new methyl thiazolyl tetrazolium assay (MTS assay) and flow cytometry. Self-renewal ability was determined by mammosphere-formation analysis. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to detect the expression of SOX2, Nanog, OCT4 and CD133. Flow cytometry analysis were further used to detect the level of CD133. IHC assays were used to detect the levels of SOX2 and CD133 in NSCLC tissues with genfitiinb resistance. Correlations of the expressions of FOXC1, CD133 and SOX2 with each other in lung adenocarcinoma samples were analyzed based on The Cancer Genome Atlas (TCGA) database.@*RESULTS@#The expression of FOXC1 is significantly increased in HCC827/GR cells compared with HCC827 cells (P<0.05). IHC results showed FOXC1 was highly expressed in NSCLC tissues with gefitinib resisitance. Knockdown of FOXC1 significantly increased the sensitivity of HCC827/GR cells to gefitinib. The cell viability was decreased and the apoptosis was promoted (P<0.05). Moreover, FOXC1 knockdown apparently inhibited the expression of SOX2 and CD133, and decreased the mammosphere-formation capacity in HCC827/GR cells. In NSCLC tissues with gefitinib resistance, the expressions of SOX2 and CD133 were significantly higher compared with gefitinib-sensitive tissues (P<0.01). Meanwhile, the expressions of FOXC1, CD133 and SOX2 with each other were positively correlated (P<0.05).@*CONCLUSIONS@#FOXC1 could increase gefitinib resitance in NSCLC, by which mechanism is related to the regulation of cancer stem cell properties.

Efficacy of gefitinib in treatment of epidermal growth factor receptor-positive advanced non-small cell lung cancer / 肿瘤研究与临床

Objective:To explore the treatment effect of gefitinib on epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC).Methods:Sixty patients with EGFR-positive advanced NSCLC who were admitted to the 904th Hospital of Joint Logistics Support Force of Chinese PLA from March 2016 to January 2020 were selected. They were divided into gefitinib treatment group (30 cases, treated with gefitinib) and combined treatment group (30 cases, treated with pemetrexed combined with cisplatin) by random number table. The anti-tumor efficacy, levels of tumor markers [serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1) and neuron-specific enolase (NSE)] before and after treatment, adverse reactions and 6-month overall survival (OS) rate were compared between the two groups.Results:The clinical control rate of gefitinib treatment group was higher than that of combined treatment group [76.7% (23/30) vs. 50.0% (15/30), χ2 = 4.593, P = 0.032]. There was no significant difference in the levels of CEA, CYFRA21-1 and NSE between the two groups before treatment (all P > 0.05). The levels of CEA, CYFRA21-1 and NSE after treatment in gefitinib treatment group were (902±41) μg/L, (3.1±0.4) ng/ml and (17.7±2.3) ng/ml. The levels of CEA, CYFRA21-1 and NSE after treatment in combined treatment group were (999±51) μg/L, (4.0±0.5) ng/ml and (19.4±3.1) ng/ml. The levels of CEA, CYFRA21-1 and NSE after treatment in gefitinib treatment group were lower than those in combined treatment group ( t = 7.441, P < 0.01; t = 7.459, P < 0.01; t = 2.486, P = 0.016).The levels of CEA, CYFRA21-1 and NSE after treatment in the two groups were all lower than those before treatment, and the differences were statistically significant (all P < 0.05). There was no significant difference in the incidence of rash, thrombocytopenia, digestive tract reaction, and proteinuria between the two groups [26.7% (8/30) vs. 23.3% (7/30), χ2 = 0.089, P = 0.766; 16.7% (5/30) vs. 13.3% (4/30), χ2 = 0.131, P = 0.718); 30.0% (9/30) vs. 26.7% (8/30), χ2 = 0.082, P = 0.774; 10.0% (3/30) vs. 13.3% (4/30), χ2 = 0.162, P = 0.688]. After 6 months of treatment, the OS rate in gefitinib treatment group was 93.3%, and that in combined treatment group was 83.3%, and there was no statistical difference between the two groups ( χ2 = 1.456, χ2 = 0.228). Conclusion:Gefitinib treatment for EGFR-positive advanced NSCLC patients can enhance the anti-tumor efficacy, reduce the content of tumor markers, and has good safety.

Expression differences of miR-200c, miR-19a and miR-155 in gefitinib sensitive and drug resistant NSCLC patients and their effects on prognosis / 国际肿瘤学杂志

Objective:To investigate the expression differences of miR-200c, miR-19a and miR-155 in gefitinib sensitive and resistant non-small cell lung cancer (NSCLC) patients, and to analyze the effects of miR-200c, miR-19a and miR-155 expression differences on the prognosis of patients.Methods:From August 1, 2015 to August 1, 2019, 80 patients with stage Ⅲ-Ⅳ NSCLC who were treated with gefitinib in the Fourth Affiliated Hospital of Nanjing Medical University were selected as the research objects. Among them, 36 cases were sensitive to gefitinib as the sensitive group, and 44 cases were resistant to gefitinib as the drug-resistant group. The general data, serum levels of miR-200c, miR-19a and miR-155 were compared between the two groups, and the sensitive factors of gefitinib in NSCLC patients and the correlations between serum miR-200c, miR-19a, miR-155 and clinicopathological characteristics of NSCLC patients were explored. The survival of the patients was analyzed.Results:Compared with the drug-resistant group, the number of smoking cases in the sensitive group was less ( χ2=5.541, P=0.019), the number of clinical stage Ⅲ cases was more ( χ2=8.984, P=0.003), the number of well-differentiated cases was more ( χ2=8.673, P=0.003), the number of patients with lymph node metastasis was less ( χ2=6.082, P=0.014), and the levels of serum miR-200c, miR-19a and miR-155 were higher ( t=7.249, P<0.001; t=8.222, P<0.001; t=10.467, P<0.001). Multivariate logistic regression analysis showed that smoking ( OR=0.355, 95% CI: 0.149-0.845, P<0.001), clinical stage ( OR=0.494, 95% CI: 0.274-0.892, P=0.021), degree of differentiation ( OR=6.062, 95% CI: 3.258-11.279, P=0.013), lymph node metastasis ( OR=0.422, 95% CI: 0.245-0.726, P=0.019), the levels of serum miR-200c ( OR=5.521, 95% CI: 3.126-9.752, P<0.001), miR-19a ( OR=5.384, 95% CI: 2.947-9.836, P<0.001) and miR-155 ( OR=5.325, 95% CI: 3.058-9.274, P<0.001) were all influencing factors of gefitinib sensitivity in NSCLC patients. The levels of serum miR-200c, miR-19a and miR-155 were significantly correlated with clinical stage ( t=3.230, P=0.002, r=-0.578; t=3.188, P=0.002, r=-0.612; t=3.123, P=0.003, r=-0.594), degree of differentiation ( t=2.586, P=0.012, r=0.610; t=4.009, P<0.001, r=0.632; t=4.773, P<0.001, r=0.594) and lymph node metastasis ( t=2.902, P=0.005, r=-0.587; t=3.721, P<0.001, r=-0.629; t=3.391, P=0.001, r=-0.614) of NSCLC patients. Compared with the patients with low levels of serum miR-200c, miR-19a and miR-155, the 1-year survival rates of the patients with high levels of serum miR-200c (63.19% vs. 4.37%, χ2=32.562, P<0.001), miR-19a (61.01% vs. 4.75%, χ2=37.807, P<0.001) and miR-155 (57.82% vs. 0, χ2=44.454, P<0.001) were higher, with statistically significant differences. Conclusion:The levels of serum miR-200c, miR-19a and miR-155 are significantly increased in gefitinib-sensitive NSCLC patients, which are important influencing factors of gefitinib sensitivity, and are closely related to clinicopathological characteristics such as clinical stage, differentiation degree and lymph node metastasis of NSCLC patients, and the prognosis is better in patients with high serum levels.

BMXΔN mediates gefitinib resistance of lung cancer cells through ERK/MAPK signaling pathway / 国际肿瘤学杂志

Objective:To explore the mechanism of a novel BMX splicing variant induced epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib resistance in lung cancer.Methods:Stable transgenic cell line PC9-BMXΔN and HCC827-BMXΔN were constructed by lentivirus infection of PC9 and HCC827 cells carrying EGFR mutation. The cells were divided into PC9-Vec group (PC9 cells transfected with empty vector), PC9-BMX group (PC9 cells stably expressing BMX), PC9-BMXΔN group (PC9 cells stably expressing BMXΔN) and HCC827-Vec group (HCC827 cells transfected with empty vector), HCC827-BMXΔN group (HCC827 cells stably expressing BMXΔN). Quantitative real-time PCR was used to detect the expression levels of mRNA. The protein expression levels in each group were detected by Western blotting. The cells in the PC9-Vec group and PC9-BMXΔN group were treated with 0, 0.01, 2.00, 50.00, 100.00, 200.00 nmol/L and 2.00, 4.00 μmol/L gefitinib. The cells in the HCC827-Vec group and HCC827-BMXΔN group were treated with 0, 0.01, 1.00, 10.00, 100.00 nmol/L and 1.00 μmol/L gefitinib. MTT method was used to detect cell viabilities.Results:The PC9-BMXΔN cells were scattered and showed a fibroblast-like morphology. Compared with the PC9-Vec cells, the relative expression levels of fibronectin, N-cadherin, vimentin, Snail, Slug and TWIST 2 mRNA in PC9-BMXΔN cells were up-regulated. Compared with the PC9-Vec cells and PC9-BMX cells, the expression levels of fibronectin and vimentin protein in PC9-BMXΔN cells were up-regulated; while the expression level of E-cadherin protein in PC9-BMXΔN cells was significantly down-regulated. Compared with the PC9-Vec cells, the cell viabilities of PC9-BMXΔN cells treated with 0.01 nmol/L [(99.11±2.16)% vs. (91.29±1.91)%, t=-4.701, P=0.011], 2.00 nmol/L [(80.41±1.48)% vs. (63.36±2.14)%, t=-11.324, P<0.001], 50.00 nmol/L [(80.83±5.38)% vs. (60.22±3.61)%, t=-5.507, P=0.005], 100.00 nmol/L [(75.54±3.46)% vs. (59.93±1.91)%, t=-6.836, P=0.002], 200.00 nmol/L [(77.57±6.53)% vs. (56.70±2.88)%, t=-5.064, P=0.007], 2.00 μmol/L [(70.22±3.45)% vs. (53.14±0.89)%, t=-8.309, P=0.001], 4.00 μmol/L [(68.66±4.67)% vs. (52.30±2.59)%, t=-4.882, P=0.008] gefitinib were significantly increased, with statistically significant differences. Similarly, compared with the HCC827-Vec cells, the cell viabilities of HCC827-BMXΔN cells treated with 1.00 nmol/L [(64.36±2.49 )% vs. (47.13±4.21)%, t=-7.067, P=0.019], 10.00 nmol/L [(63.25±5.87)% vs. (43.28±2.95)%, t=-5.267, P=0.006], 100.00 nmol/L [(49.47±5.74)% vs. (37.12±4.92)%, t=-2.830, P=0.047], 1.00 μmol/L [(49.05±3.34)% vs. (32.06±4.73)%, t=-5.073, P=0.007] gefitinib were significantly increased, with statistically significant differences. Gefitinib treatment could significantly inhibit the expression levels of p-EGFR and p-ERK1/2 both in PC9-Vec cells, PC9-BMX cells and PC9-BMXΔN cells. Compared with the PC9-Vec cells and PC9-BMX cells, the expression level of p-EGFR in PC9-BMXΔN cells was significantly increased after gefitinib treatment for 8 h (0.91±0.04 vs. 0.81±0.04 vs. 0.80±0.05, all P<0.05); the expression levels of p-ERK1/2 in PC9-BMXΔN cells were significantly increased after gefitinib treatment for 2 h (0.64±0.06 vs. 0.38±0.12 vs. 0.37±0.14), 4 h (1.28±0.06 vs. 1.08±0.06 vs. 1.11±0.07), and 8 h (0.75±0.04 vs. 0.55±0.05 vs. 0.60±0.07), with statistically significant differences (all P<0.05). Conclusion:BMXΔN is involved in EGFR-TKI gefitinib resistance in lung cancer, which may be achieved by inducing cells to undergo epithelial-mesenchymal transition and activating the ERK/MAPK signaling pathway.

The effect of kanglaite injection in combination with gefitinib versus gefitinib alone in patients with nonsmall cell lung cancer: A meta-analysis

Objective: The objective of the study was to evaluate the clinical efficacy of kanglaite (KLT) injection combined with gefitinib versus gefitinib alone in the treatment of nonsmall cell lung cancer (NSCLC). Methods: The randomized controlled trials involving NSCLC treatment with KLT injection combined with gefitinib versus gefitinib alone were searched on seven medical databases up to October 2016. Two reviewers independently assessed the methodological quality of the included studies. The RevMan 5.3 software was employed for data analysis. Results: Seven randomized trials involving 554 patients met our criteria. Compared with gefitinib alone, KLT injection combined with gefitinib showed significant effects in increasing objective response rate (relative risk [RR] =1.38; 95% confidence interval [CI], 1.09–1.75), improving the performance status (RR = 1.80; 95% CI: 1.34–2.42), raising the percentages of CD4+ cells (weighted mean difference [WMD] = 4.45; 95% CI: 2.61–6.28), natural killer cells (WMD = 4.43; 95% CI: 3.85–5.01), and ratio of CD4+/CD8+ (WMD = 0.08; 95% CI: 0.02–0.14), whereas the difference was not significant in gefitinib toxicity including rash (RR 0.90; 95% CI: 0.58–1.40, P = 0.65), diarrhea (RR 1.04; 95% CI: 0.66–1.64, P = 0.88), and liver injury (RR 1.00; 95% CI: 0.58–1.73, P = 1.00), CD3+ cells (WMD = 1.16; 95% CI: -2.64–4.97) and CD8+ cells (WMD = 6.78; 95% CI: -1.68–15.23). Conclusion: Co-use of KLT injection and gefitinib may benefit the patients with NSCLC through enhancing the therapeutic effectiveness compared with gefitinib alone. To confirm these results, further rigorously designed trials are warranted

Comparative efficacy and safety of first-line EGFR-TKIs for advanced non-small cell lung cancer：a network meta-analysis / 中华疾病控制杂志

Objective To compare the efficacy and safety of gefitinib, erlotinib, and afatinib in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Methods PubMed, EMBASE, and The Cochrane Library were searched to identify the relevant literatures published from December 2008 to December 2018. Bayesian network meta-analysis was carried out to rank the three treatments. Results A total of ten eligible studies involving 2275 patients were enrolled. In terms of efficacy, the surface under the cumulative ranking (SUCRA) indicated that erlotinib performed best in progression-free survival(PFS)(0.88), afatinib performed best in objective response rate(ORR)(0.82) and disease control rate(DCR) (0.86), gefitinib performed worst in PFS (0.45), ORR(0.42), and DCR(0.45). For safety, the differences of grade 3 or 4 adverse events rate (OR=0.29,95%CI:0.08-0.98) and discontinuation rate(OR=0.14,95%CI:0.01-0.8) between erlotinib and the platinum-based doublet chemotherapy were statistically significant. The ranking results also supported that erlotinib was the safest. SUCRA results suggested that gefitinib (0.31) had a lower grade 3 or 4 adverse events rate than afatinib (0.57), and the possibility of discontinuation in gefitinib (0.44) was similar to that of afatinib (0.41). Conclusion Erlotinib might be the preferred first-line treatment for advanced NSCLC after weighing and balancing the benefits and risks.

Establishment of gefitinib resistant lung cancer cell line and changes of EGFR signaling pathway / 中国药理学通报

Aim To establish gefitinib resistant epidermal growth factor receptor(EGFR) mutant lung cancer cell lines and to explore the changes of downstream signaling pathway of EGFR. Methods Gefitinib concentration gradient method was used to induce the establishment of H3255 and HCC827 resistant cell lines, and CCK8 assay was used to detect the proliferation of gefitinib resistant cell lines H3255/GR and HCC827/ GR. Western blot was used to detect the changes of EGFR downstream signals in H3255, HCC827, H3255/GR and HCC827/GR cells. Results The proliferation of H3255/GR and HCC827/GR cells was significantly lower than that of non-drug resistant cells. The phosphorylation signal molecules p-AKT, p-ERK1/2 and p-STAT3 of H3255/GR and HCC827/ GR drug-resistant cell lines were no significantly changed compared with their non-drug-resistant cell lines. There was no significant change in the expression of p-STAT3 and p-ERKl/2 in H3255/GR cells treated with gefitinib, but the expression of p-AKT was significantly down-regulated, while gefitinib only slightly inhibited the expression of p-ERKl/2 in drugresistant H3255/GR cells. In HCC827/GR cells, p-AKT and p-STAT3 were not inhibited by gefitinib, while p-ERKl/2 was moderately inhibited. Conclusion There are significant differences in the signal mechanism of drug resistance between H3255/GR and HCC827/GR cell lines.

Analysis of Drug Use for Rare Gefitinib-caused Liver Injury Complicated with Cholecystitis in a Patient with Lung Adenocarcinoma by Clinical Pharmacists / 中国药房

OBJECTIVE：To investigate the role of clinical pharmacists in the therapy of gefitinib-caused liver injury complicated with cholecystitis in a patient with lung adenocarcinoma ，and to provide reference for the therapy of similar type of patients. METHODS ： Clinical pharmacists participated in the treatment for gefitinib-caused liver injury complicated with cholecystitis in a patient with lung adenocarcinoma. The patient took Gefitinib tablets orally for a long time for anti-tumor treatment，and was hospitalized due to abnormal increase of transaminase. The doctors gave intravenous infusion of tiopronin sodium+ acetylcysteine+reduced glutathione+citicoline to protect liver ，but the effect was not good. After consulting the literature and analyzing the patient ’s condition ， clinical pharmacists suggested that gefitinib should be stopped ， and Magnesium isoglycyrrhizinate injection 0.2 g+5％ Glucose injection 250 mL，ivgtt，qd for liver protection treatment. After discharge ，the patient took Gefitinib tablets orally and was admitted to hospital again due to abnormal increase of transaminase ，and suffered from non-infectious and non-calculous cholecystitis. Clinical pharmacists suggested continuing intravenous drip of Magnesium isoglycyrrhizinate injection 0.2 g+5％ Glucose injection 250 mL，qd for liver protection treatment ，oral administration of Danshu capsules 0.9 g，tid for conservative treatment ；at the same time ，closely monitoring the changes of related indicators. After discharge，clinical pharmacists instructed patients to stop gefitinib ，and take Icotinib hydrochloride tablets 0.125 g，tid+Compound Taxus capsules 0.6 g，tid for anti-tumor treatment. RESULTS ：The doctors adopted the opinions of clinical pharmacists ，and the transaminase levels returned to normal ，and the symptoms of cholecystitis basically subsided. CON CLUSIONS：In the treatment of gefitinib-caused liver injury complicated with cholecystitis in patients with lung adenocarcinoma ， clinical pharmacists 135） assisted doctors to improve the treatment plan and ensure the effectiveness of drug use.

Gefitinib inhibits glycolysis and induces programmed cell death in non-small cell lung cancer cells / 南方医科大学学报

OBJECTIVE@#To observe the cell death pattern induced by gefitinib in non-small cell lung cancer A549 and H1975 cells and explore the possible mechanism in light of glycolysis.@*METHODS@#The inhibitory effects of gefitinib at 20, 30, or 40 μmol/L in A549 cells and at 20, 40, or 80 μmol/L in H1975 cells were examined using MTT assay. The changes of lactic acid level in the cells were determined with a lactic acid kit, and the expression levels of glycolysis-related proteins (PKM2 and HK2) and the proteins in PI3K-Akt-mTOR signaling pathway were detected using Western blotting. 2-NBDG was used for detecting glucose uptake capacity of the cells, and ATP kit was used to detect the intracellular ATP level. The mitochondrial membrane potential of the cells was examined with the JC-1 kit, and cell apoptosis was analyzed with Annexin V-FITC/PI double staining. The relative expression levels of the apoptotic proteins Bax and Bcl-2 and the autophagy marker protein LC3B were detected with Western blotting.@*RESULTS@#MTT assay showed that gefitinib inhibited the proliferation of A549 and H1975 cells in a time- and dose-dependent manner ( < 0.05). The IC of gefitinib at 24, 48 and 72 h was 48.6, 28.6 and 19.7 μmol/L in A549 cells and was 321.6, 49.1 and 14.6 μmol/L in H1975 cells, respectively. Gefitinib significantly lowered intracellular lactic acid level of the cells ( < 0.05) and down-regulated the expressions of PKM2 and HK2 proteins ( < 0.05) and PI3K-Akt-mTOR signaling pathway-associated proteins ( < 0.05). Gefitinib obviously inhibited glucose uptake and ATP levels in both A549 and H1975 cells ( < 0.05). Treatment with gefitinib induced obviously enhanced apoptosis in the cells, resulting in apoptosis rates of (10.77± 1.0)%, (14.5±0.4)%, (17.4±0.2)% and (32.1±0.6)% at 0, 20, 30 and 40 μmol/L in A549 cells ( < 0.05) and of (10.5±0.6)%, (13.2± 0.92)%, (18.9±0.98)% and (35.1±1.4)% at 0, 20, 40 and 80 μmol/L in H1975 cells, respectively ( < 0.05). The protein expression of Bax increased and that of Bcl-2 decreased following gefitinib treatment in the cells ( < 0.05). Gefitinib significantly increased autophagy in A549 and H1975 cells as shown by increased LC3B expressions following the treatment ( < 0.05).@*CONCLUSIONS@#Gefitinib can inhibit the proliferation, induce apoptosis and increase autophagy in A549 and H1975 cells. Gefitinib induces apoptosis of the cells possibly by affecting glycolysis and PI3K-Akt-mTOR signaling pathway.

Synergistic Anti-cancer Effect and Mechanism of FZKA Decoction Combined with Gefitinib on A549 Cells / 中国实验方剂学杂志

Objective::To observe the effect of Fuzheng Kangai (FZKA) decoction combined with gefitinib on the cells proliferation, apoptosis, invasion and metastasis of human lung adenocarcinoma A549 cells in vitro and in vivo, and relevant mechanisms. Method::The A549 cell proliferation of the control group, FZKA decoction groups (0.2, 0.4, 0.8, 1.6, 3.2 g·L-1), Gefitinib groups (10, 20, 40, 60, 80, 100 μmol·L-1) for 24, 48, 72 hours, and FZKA decoction (2 g·L-1) combined with Gefitinib (10 μmol·L-1) groups for 24 hours was detected by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The changes of cell apoptosis, invasion and metastasis abilities of A549 cells were analyzed by flow cytometry, Wound Healing, transwell invasion assay. Western blot assay was used to examine the protein expressions of cleaved Caspase-3, B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-2 associated X (Bax), F-box and WD repeat domain-containing (FBW7) and myeloid cell leukemia-1 (MCL-1) in vitro. Result::Compared with control group, FZKA decoction group and Gefitinib group inhibited the cell proliferation, cell apoptosis, cell invasion and metastasis abilities in a dose-dependent and time-dependent manner, and improve the protein expressions of Bax, Caspase-3, FBW7, but decreased the protein expressions of Bcl-2, MCL-1 (P<0.05). Compared with treatment with Gefitinib alone, FZKA combined with Gefitinib inhibited the proliferation of A549 cells, and induced apoptosis more significantly (P<0.05). Compared with treatment with Gefitinib alone, the cell scratch healing and invasion abilities were significantly reduced after combined treatment (P<0.05). FZKA decoction combined with Gefitinib up-regulated Bax, Caspase-3 and FBW7 protein expressions, and down-regulated Bcl-2 and MCL-1 protein expressions compared with treatment with Gifitinib alone (P<0.05). Conclusion::FZKA decoction combined with Gefitinib can inhibit the proliferation, invasion and metastasis, and induce apoptosis on A549 cells. The mechanism may be associated with the FBW7/MCL-1 pathway.

miR-125a-5p promotes the resistance to gefitinib in non-small cell lung carcinoma cells by targetingAPAF1 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective:ToinvestigatetheroleofmiR-125a-5pininducingthegefitinib(Gef)-resistance of non-small cell lung carcinoma (NSCLC) cells and its possible mechanism. Methods: Human NSCLC drug-resistant cell line A549/GR and NSCLC cell line A549 were chosen for this study. miR-125a-5p mimic, miR-125a-5p inhibitor, pcDNA3.1-APAF1 and empty vector pcDNA3.1 were transfected into A549/GR cells. The expression level of miR-125a-5p in cell lines was detected by qPCR. MTT, Transwell and Flow cytometry were used to detect the effects of Gef on proliferation, migration and apoptosis of cell lines, respectively. The targeting relationship between miR-125a-5p and APAF1 (apoptotic peptidase activating factor 1) was verified by Dual-luciferase reporter gene system. In addition, the expression of APAF1 protein in A549/GR cells was detected by Western blotting. The expression levels of caspase-3 and caspase-9 were assessed by colorimetry. Results: Expression level of miR-125a-5p was upregulated significantly in Gefresistant A549/GR cells (P<0.01). AndtheinfluencesofGefonA549/GRcellswereenhancedby knockdown of miR-125a-5p, including inhibiting cell proliferation and migration (all P<0.05) and inducing apoptosis (P<0.01). Dual luciferase reporter gene assay confirmed that miR-125a-5p targeted APAF1 and negatively regulated its expression. Furthermore, by targetedly downregulating APAF1, miR-125a-5p alleviated the inhibition of proliferation and migration (all P<0.05) and promotion of apoptosis (P<0.05) of A549/GR cells caused by Gef, and attenuated Gef-induced upregulation of apoptosis-related proteins caspase-3 and caspase-9 (all P<0.05). Conclusion: miR-125a-5p promotes Gef-resistance of A549/GR cells, and the underlying mechanisms are promotion of proliferation, migration and inhibition of apoptosis of non-small cell lung cancer cells by targetingAPAF1.