Research Progress on the Combination Therapy of EGFR-TKIs and Metformin in Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR are effective in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. With the application and expansion of individualized and combined therapy, more and more studies have shown that combined administration of Metformin effectively solves the problem of acquired drug resistance to EGFR-TKIs in clinical treatment and prolongs the survival of patients with NSCLC. EGFR-TKIs combined with Metformin is expected to be the treatment method of choice for NSCLC patients with EGFR-TKIs resistance. This paper intends to summarize the research progress of EGFR-TKIs combined with Metformin in the treatment of EGFR-TKIs acquired resistance in NSCLC, in order to provide a new idea for the treatment of NSCLC patients with acquired resistance to EGFR-TKIs.
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Progress in epidermal growth factor receptor-tyrosine kinase inhibitors-associated interstitial lung disease / 中国胸心血管外科临床杂志

@#The tyrosine kinase activity of epidermal growth factor receptor (EGFR) plays a key role in tumor cell proliferation, invasion, migration, and drug resistance. Studies have shown that non-small cell lung cancer patients with somatic driver gene EGFR mutations are sensitive to and can benefit from EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Nevertheless, EGFR-TKIs-related adverse events should not be ignored. Common adverse events such as diarrhea, acne-like rash and paronychia are usually manageable; although the incidence of interstitial lung disease is low, once it occurs, it is a serious threat to patients' life, and its pathogenesis is still unclear. There is very limited animal experimental and clinical research evidence on the potential mechanism of EGFR-TKIs-related interstitial lung disease in the available literature. Based on this, this article reviews the association between EGFR-TKIs and interstitial lung disease, at the same time, also discusses the research progress of EGFR-TKIs-related interstitial lung disease in combination with cytotoxic drugs or immunotherapeutic drugs and EGFR-TKIs, in order to provide a reference for the prevention and treatment of EGFR-TKIs-related interstitial lung disease in clinical practice in the future.

Clinical observation of bevacizumab versus anlotinib respectively combined with chemotherapy drug in the treatment of EGFR-TKI acquired resistant advanced lung adenocarcinoma / 中国药房

OBJECTIVE To compare the short-term therapeutic effect and safety of bevacizumab versus anlotinib respectively combined with chemotherapy drug in the treatment of epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKI） acquired resistant advanced lung adenocarcinoma. METHODS The information of 84 patients with EGFR-TKI acquired resistant advanced lung adenocarcinoma in the Third People’s Hospital of Chengdu was analyzed retrospectively during Jun. 2019-Oct. 2021. The patients were divided into chemotherapy group （32 cases）， anlotinib combined chemotherapy group （24 cases） and bevacizumab combined chemotherapy group （28 cases）. Patients in the chemotherapy group were given Pemetrexed disodium for injection and Carboplatin injection， and symptomatic treatment was given for adverse reactions. On the first day of chemotherapy， patients in the anlotinib combined chemotherapy group received Anlotinib hydrochloride capsules 10 mg orally， once a day， for 14 consecutive days and 7 days of discontinuation， based on the treatment of the chemotherapy group. Patients in the bevacizumab combined chemotherapy group were given Bevacizumab injection of 15 mg/kg intravenously 1 day before chemotherapy， based on the treatment of the chemotherapy group. Three groups of patients were treated for a total of four cycles， with one cycle every three weeks. The overall response rate （ORR）， disease control rate （DCR）， median progression-free survival （mPFS）， and the changes of serum tumor markers were compared among three groups before and after treatment； meanwhile， the occurrence of adverse drug reactions was recorded， and the 1-year survival rate was followed up. RESULTS After 4 treatment cycles， ORR and DCR of bevacizumab combined chemotherapy group and anlotinib combined chemotherapy group were higher than chemotherapy group （P＜0.05）； mPFS of the two groups were significantly longer than chemotherapy group， and DCR of anlotinib combined chemotherapy group was significantly higher than bevacizumab combined chemotherapy group （P＜0.05）. After 4 treatment cycles， the serum levels of tumor markers in three groups were significantly lower than before treatment， and both combined chemotherapy groups were significantly lower than chemotherapy group （P＜0.05）. There was no statistically significant difference in the incidence of adverse reactions such as nausea， vomiting， bone marrow suppression， and 1-year survival rate among the three groups of patients （P＞0.05）. CONCLUSIONS Bevacizumab and anlotinib combined with chemotherapy drug are effective and safe in the treatment of advanced lung adenocarcinoma with acquired EGFR-TKI resistance.

A review: drug-drug interactions of epithelial growth factor receptor-tyrosine kinase inhibitors / 中华肿瘤杂志

Mutations in the epithelial growth factor receptor (EGFR) is a driving factor that causes non-small cell lung carcinoma (NSCLC). The epithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a crucial discovery in the treatment of lung cancer, particularly the efficacy of EGFR-TKIs is superior to that of the standard chemotherapy for patients with EGFR mutation-positive advanced NSCLC. Patients with NSCLC use EGFR-TKIs and other medications simultaneously is commonly seen, especially among those with comorbidities, which increases the risk of drug-drug interactions (DDIs) of EGFR-TKIs. The most common mechanisms underlying the DDIs of EGFR-TKIs are modulations of cytochrome P450 (CYP) and drug transporters [including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)], as well as gastrointestinal acid-inhibitory drugs [proton pump inhibitors (PPIs) and H(2) receptor antagonists (H(2)RA)]. Inhibitors or inducers of CYP enzymes and drug transporters can inhibit or accelerate the metabolism of EGFR-TKIs, which increase or reduce the exposure of EGFR-TKIs, thereby affect the efficacy and safety of EGFR-TKIs. In addition, PPIs or H(2)RA can decrease the solubility, bioavailability and efficacy of EGFR-TKIs. This review summarizes the mechanisms of DDIs of gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib; the management recommendations for DDIs of those EGFR-TKIs from the Chinese and global guideline, as well as from the recent pre-clinical and clinical studies, which provide the reference and evidence for managing the combination therapies of EGFR-TKIs and other medications in clinics.

Research Progress of New Generation EGFR-TKIs after Third-generation / 中国肺癌杂志

Lung cancer has the highest mortality rate in the world. The first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival time and quality of life of patients with non-small cell lung cancer (NSCLC) to some extent. However, after a period of progression-free survival, most patients develop drug resistance, in which T790M mutation is the mainly resistance mechanism. The third-generation EGFR-TKIs, represented by osimertinib, are found to have significant effect on this resistance. The effect is remarkable, but drug resistance is still inevitable. For example, C797S mutation, mesenchymal-epithelial transition (MET), RAS mutation, BRAF mutation, transformation of small cell lung cancer (SCLC), transformation of epithelial mesenchymal transition (EMT), etc. But, there is no standard and effective treatment after the third-generation EGFR-TKIs resistance. In this view, we summarize the research progress in the new generation EGFR-TKIs after third-generation, in order to provide some reference for the follow-up research and treatment.
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Clinical Predictive Factors associated with First Line EGFR-TKI Efficacy in Advanced NSCLC Patients with EGFR Mutations / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated some dramatic efficacy in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, progression-free survivals (PFS) among those patients who were treated with first line EGFR TKIs were inconsistent. The aim of this study is to explore the association of clinical prognostic factors with EGFR-TKI efficacy in advanced NSCLC patients.@*METHODS@#The demographic and clinical characteristics of 203 patients with activating EGFR mutation treated with first generation TKI as a first-line therapy were retrospectively reviewed.@*RESULTS@#Of the 203 patients enrolled in this study, 139 patients had progression of disease and 63 patients died. The subjects had a median follow up duration of 21.1months and a median PFS of 14.3 months. Partial response (PR) was achieved in 127 (66.1%) patients and stable disease (SD) rate was achieved in 55 (28.6%) patients. In univariate analysis, patients with 2 or higher ECOG score (5.1 vs 16 months, P=0.033), SD as best overall response (9.5 vs 17.9 months, P=0.030), extrathoracic metastasis (11.7 vs 27.5 months, P=0.004), liver metastasis (4.1 vs 16.0 months, P=0.000), bone metastasis (13.3 vs 21.5months, P=0.027) and pulmonary embolism (5.5 vs 16.6 months, P=0.005) had shorter PFS than those without the listed factors. Multivariable Cox regression analysis showed best overall response (HR=1.825, 95%CI: 1.107-3.008, P=0.018) and liver metastasis (HR=1.694, 95%CI: 1.146-5.756, P=0.022) were independent predictive factors of shorter PFS.@*CONCLUSIONS@#Despite the high efficacy of EGFR-TKI, SD as best overall response and liver metastasis predicts poorer PFS in advanced NSCLC patients with EGFR gene mutations receiving first-line therapy treatment.

Plasma relative abundance of epidermal growth factor receptor mutations predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma / 中华内科杂志

Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study, adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumor tissues were detected by ADx-amplification refractory mutation system (ADx-ARMS). EGFR mutations of plasma free tumor DNA were detected by ADx-ARMS and ADx-super amplification refractory mutation system (ADx-SuperARMS) at the same time. Patients with EGFR-mutant in tumor tissues and receiving EGFR-TKIs were finally enrolled. Plasma mutation-positive patients with both methods were high abundance group.Patients with positive mutations by ADx-SuperARMS but negative by ADx-ARMS were medium abundance group. Mutation-negative patients with both methods were recognized as low abundance group. The correlation between EGFR mutation abundance and clinical response to EGFR-TKIs were analyzed. Results Among 71 patients enrolled, 42 harbored EGFR mutations in plasma were detected by ADx-ARMS, while 53 were found by ADx-SuperARMS.There were 42 patients in high abundance group, 11 in medium group while the other 18 in low group. The objective response rates (ORRs) were 69.0%,7/11 and 10/18 in high, medium and low groups, respectively. The difference was significant between high and low abundances groups (P=0.006). Median progression-free survival (PFS) in high,medium and low groups were 11.0, 8.5 and 9.0 monthes, respectively (P<0.001). In patients with tumor 19-Del, the ORRs were 70.4%,5/7 and 6/11 in high,medium and low abundance groups, respectively. The median PFS of high abundance group was significantly longer than the other two groups (12.0 monthes vs 9.0, 9.0 monthes). As to subjects with L858R mutation, the ORRs were 10/15,2/4 and 3/6,respectively, with median PFS 9.6, 5.5 and 9.5 monthes. Conclusions The relative abundance of EGFR mutations in plasma predicts clinical response to EGFR-TKIs in patients with advanced lung adenocarcinoma. The higher the mutation abundance is, the better the efficacy of EGFR-TKIs is.

Treatment of non-small cell lung cancer with EGFR-TKI / 国际肿瘤学杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the key to the treatment of advanced non-small cell lung cancer (NSCLC),but there are various drug-resistant mutations in the latter stage.The first and second generation of EGFR-TKIs significantly prolong the survival of patients with EGFR-activated mutant tumors.The third generation of EGFR-TKIs effectively inhibit the progress of T790M mutant tumors.The fourth generation of EGFR-TKIs inhibit both L858R,T790M and L858R,T790M,C797S mutant tumors.Using circulating tumor DNA and exogenous RNA can effectively detect the mutation types of EGFR,and choose EGFR-TKIs therapy or combined chemotherapy according to the mutation types.

Application value of serum LDH in advanced non-small cell lung cancer patients treated with EGFR-TKI / 国际肿瘤学杂志

Objective To investigate the value of serum lactate dehydrogenase (LDH) in advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI).Methods Pretreatment LDH level,pathological characteristic,tumor staging and treatment situation of 190 advanced NSCLC patients with EGFR sensitive mutation confirmed by pathology were retrospectively collected in Zhuhai People's Hospital of Guangdong Provice from July 2011 to July 2015.All the patients were divided into LDH normal group (LDH ≤252 U/L,n =78) and elevated group (LDH ＞ 252 U/L,n =112) according to pretreatment LDH level.Inaging evaluations of the patients were performed regularly,and the progression-free survival (PFS) and overall survival (OS) were recorded.The survival curves were plotted by Kaplan-Meier method and survival difference between patients with different LDH level was compared by logrank test.Cox regression analysis was used to analyze prognostic factors for mortality.Results The objective response rate of the LDH normal group was 76.9％ (60/78),and the elevated group was 71.4％ (80/112),with no statistically significant difference (x2 =0.716,P =0.398).The disease control rate of the LDH normal group was 89.7％ (70/78),and the elevated group was 85.7％ (96/112),with no statistically significant difference (x2 =0.676,P =0.411).The median PFS of the LDH normal group was 11.5 months,and the elevated group was 9.7 months (x2 =5.92,P =0.015).The median OS was 31.0 months in the LDH normal group,and 26.1 months in the elevated LDH group (x2 =4.79,P =0.029).Both PFS and OS of patients with elevated LDH were shorter than those of patients with normal LDH.Cox multivariate regression analysis showed that tumor staging (HR =1.652,95％ CI:1.386-2.259,P =0.018),PS score (HR =2.248,95％ CI:1.507-3.846,P ＜ 0.001),carcino-embryonic antigen (CEA) level (HR =1.250,95％ CI:1.066-1.703,P =0.037) and LDH level (HR =1.771,95 ％ CI:1.324-1.947,P =0.015) were independent prognostic factors in patients with advanced NSCLC.Conclusion Pretreatment serum LDH can not affect the objective response rate and disease control rate of EGFR-TKI in the treatment of advanced NSCLC,but can affect the PFS and OS of patients.Pretreatment serum LDH is an independent prognostic factor.

Application of radiomics captured from CT to predict the EGFR mutation status and TKIs therapeutic sensitivity of advanced lung adenocarcinoma / 中华肿瘤杂志

Objective@#To explore the ability of computed-tomography (CT) radiomic features to predict the Epidermal growth factor receptor (EGFR) mutation status and the therapeutic response of advanced lung adenocarcinoma to EGFR- Tyrosine kinase inhibitors (TKIs) treatment.@*Methods@#A retrospective analysis was performed on 253 patients diagnosed as advanced lung adenocarcinoma, who underwent EGFR mutation detection, and those with EGFR sensitive mutation were treated with TKIs. Using the Lasso regression model and the 10 fold cross-validation method, the radiomic features of predicted EGFR mutation status and the screening of TKIs for sensitive populations were obtained. 715 radiomic features were extracted from unenhanced, arterial phase and venous phase, respectively.@*Results@#The area under curve (AUC) values of the multi-phases including unenhanced, arterial phase and venous phase of the EGFR mutation status validation group were 0.763, 0.807 and 0.808, respectively. The number of radiomic features extracted from the multi-phases were 5, 18 and 23, respectively, which could distinguish the EGFR mutation status. The AUC values of the multi-phases of the EGFR-TKIs sensitive validation group were 0.730, 0.833 and 0.895, respectively. The number of radiomic features extracted from the multi-phases were 3, 7 and 22, respectively, which can be used to screen the superior population for TKIs treatment. The efficiency of radiomic features extracted from venous phase in predicting EGFR mutant status and EGFR-TKIs sensitivity was significantly superior than those of unenhanced and arterial phase.@*Conclusions@#The radiomic features of CT scanning can be used as the radiomics biomarker to predict the EGFR mutation status of lung adenocarcinoma and to further screen the dominant population in TKIs therapy, which provides the basis for targeted therapy.

Advances in Long Non-coding RNAs on Resistant to EGFR-TKIs in Non-small Cell Lung Cancer / 中国肺癌杂志

Most non-small cell lung cancer patients with active epidermal growth factor receptor (EGFR) mutation will eventually acquire drug resistant to EGFR tyrosine kinase inhibitors, such as gefitinib, resulting in disease progression, which involves a variety of complex mechanisms. Up to now, the molecular mechanisms of long non-coding RNAs mediated EGFR-TKIs resistance remains poorly understood. This review aims to outline the current state of information on lncRNAs and progress on its role in EGFR-TKIs resistance in non-small cell lung cancer.

Clinical outcomes of epidermal growth factor receptor tyrosine kinase inhibitors in re-current adenosquamous carcinoma of the lung after resection / 中国肿瘤临床

Objective:To investigate the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in adenosqua-mous carcinoma (ASC) of the lung after resection. Methods:Clinical data of patients suffering from ASC and receiving EGFR-TKI treat-ment at one institution between January 2006 and December 2014 were retrospectively reviewed. Results:A total of 27 EGFR muta-tion-positive patients with ASC subjected to EGFR-TKI therapy were enrolled in this study. EGFR mutations included deletion in exon 19 in 15 cases and point mutation at codon 858 in exon 21 in 12 cases. Of the 27 ASC patients who received EGFR-TKI treatment, 9 exhibit-ed a partial response and 11 manifested a stable disease, and these patients accounted for a disease control rate of 74.1%(20/27). The median overall survival (OS), median progression-free survival, and median relapse OS of the EGFR mutation-positive patients who underwent TKI therapy were 39 months [95%confidence interval (CI)=25.6-52.4], 15 months (95%CI=12.9-17.1), and 19 months (95%CI=0.9-37.1), respectively. The 3-and 5-year survival rates of these patients after operation were 51.9%and 15.3%, respectively. Con-clusion:The survival of EGFR mutation-positive ASC patients treated with EGFR-TKIs was satisfactory. EGFR testing was recommended for ASCs and EGFR-TKI treatment was suitable for ASCs with EGFR-sensitizing mutation.

Influence of EGFR-TKIs on T Lymphocyte Subsets and Its Efficacy in the Treatment of Patients with Advanced Non-small Cell Lung Cancer / 中国药师

Objective: To observe the influence of epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) on peripheral blood T lymphocyte subsets, and its efficacy and safety in the treatment of non-small cell lung cancer (NSCLC) patients.Methods: A total of 35 cases with NSCLC in our hospital were selected as the observation group and 28 healthy persons undergoing health examination at the same time were used as the control group.All the NSCLC patients were with EGFR mutations and accepted the EGFR-TKIs therapy.Flow cytometry was employed to detect T lymphocyte subsets in peripherial blood (including CD3+,CD4+,CD8+,CD4+/CD8+ and NK lymphocy-tes)in one week before the treatment, at the 1st, 2nd and 4th cycle after the EGFR-TKIs treatment, and the curative effect and safety were evaluated as well.Results: Before the chemotherapy, the levels of CD3+, CD4+, CD4+/CD8+ and NK lymphocytes in the NSCLC patients were significantly lower than those in the control group (PSD>PD.The adverse reactions caused by EGFR-TKIs were slight, and all could be improved markedly after the symptomatic treatment.Conclusion: EGFR-TKIs can significantly regulate the expression of T lymphocyte subsets in NSCLC patients and improve the immune function of the patients with promising safety.

Mechanism and clinical efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer / 中华肿瘤杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR-TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients.

Role of cancer stem cells in EMT-induced acquired resistance to EGFR-TKIs in NSCLC cells / 实用医学杂志

Objective To explore the role of cancer stem cells in EMT-induced acquired resistance to EGFR-TKIs in NSCLC. Methods The EGFR del E746-A750 mutated human lung adenocarcinoma PC-9 cell line and gefitinib acquired resistance cell line PC-9/AB were used in this study. EMT was assessed by western blotting assay. The sensitivity to gefitinib was tested with CCK8. Flow cytometry for antibody analysis was used to quantify CSCs within the cell lines. Results Compared with PC-9, PC-9/AB underwent EMT and showed no-table resistance to gefitinib (P < 0.01). Compared with PC-9, the proportions of CSCs were much higher in PC-9/AB. Conclusion EMT plays an important role in the acquired resistance to EGFR-TKIs in NSCLC , possibly through the up-regulation of CSCs.

Tumor volume recession pattern of patients with non-small cell lung cancer before and after EGFR-TKI targeting treatment and its clinical value / 吉林大学学报(医学版)

Objective:To explore the regular variation pattern of tumor volumes of the patients with non-small cell lung cancer (NSCLC) before and after targeting treatment of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI),and to clarify its clinical value.Methods:The materials of 39 NSCLC patients with EGFR-TKI targeting treatment were retrospectively analyzed. The tumor volumes were detected by volume measurement software of TPS and Image J image processing software,then the absolute and relative tumor volume changes of the NSCLC patients before and after targeting treatment were analyzed by paired sample comparison symbol Wilcoxon rank test. Results:The absolute tumor volumes (mm3 )of the patients with NSCLC before and 1 month after targeting treatment were 14 822.11 (7 524.73,54 999.41)and 7 954.42 (3 499.73,29 396.83),respectively, and there was statistically significant difference (Z=-3.257,P=0.001);the absolute tumor volumes of the patients with NSCLC 1 and 2 months after targeting treatment were 8 358.47 (4 394.36,24 430.05)and 7 028.76 (3 634.98,21 056.71),respectively,and there also was statisticaliy significant difference (Z=-2.213,P=0.027).When the original tumor volume before targeting treatment was regarded as 1,the relative tumor volume of 1 month after targeting theatment was 0.612 6 (0.313 8,0.853 7),and there was significant difference (Z=-3.855,P0.05);the changes of tumor relative volume presented platform stage after 3 months.The tumor relative volumes of 7-9 months after EGFR-TKI treatment reached the bottom.Conclusion:The average primary tumor volume of the NSCLC patients is obviously reduced 1 and 2 months after TKI targeting treatment. It may be optimal to carry out radiotherapy in 3-9 months after EGFR-TKI targeting treatment.

Research progress on Chinese materia medica in overcoming EGFR-TKIs acquired drugs resistance through PI3K/Akt/mTOR pathway / 中草药

With in-depth study of the pathogenesis of lung cancer and its biological behaviour, molecular targeted therapy, especially the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) made a breakthrough in non-small cell lung cancer treatment. However, the majority of patients can produce the resistance to EGFR-TKIs after 6 to 12 months treatment, which called acquired drug resistance. PI3K/Akt/mTOR pathway plays an important role in the development of non-small cell lung cancer, this pathway in cancer treatment has been widely studied. Chinese materia medica (CMM) in overcoming EGFR-TKIs resistance has a bright future, In this review, we show the developments on CMM in overcoming EGFR-TKIs acquired drugs resistance through PI3K/Akt/mTOR pathway.

Correlation of E-cadherin Expression and the Sensitivity to EGFR-TKI Molecular Targeted Therapy / 医药导报

Objective To explore the correlation of E-cadherin expression and the sensitivity to EGFR-TKI molecular targeted therapy. Methods Eight kinds of cells,MCF-7,MDA-MB-231,T24,SiHa,H460,SK-HEP-1,MHCC97-H and THP-1 were treated with EGFR-TKI PD153035 and gefitinib,respectively,for 48 hours. The drug-sensitivity was detected by MTT,and the IC50 of cells were calculated. The E-cadherin protein were detected and compared. Results Followed with PD153035 and gefitinib treatment,the survival rates of MCF-7,MDA-MB-231,T24 and SiHa significantly reduced,and more E-cadherin protein expressed. However, the survival rates of the H460, SK-HEP-1, MHCC97-H, and THP-1 cells showed opposite results. Conclusion The sensitivity of epithelial cancer cells to EGFR-TKI is correlated with E-cadherin expression. E-cadherin may play a significant role on regulateing the sensitivity to EGFR-TKI molecular targeted therapy. E-cadherin is a key biomarker for recruiting appropriate patients for EGFR-TKI molecular targeted therapy.

Relationship between EGFR protein phosphorylation,EGFR mutation and EGFR-TKI efifcacy in advanced non-small cell lung cancer / 中国癌症杂志

Background and purpose:EGFR-TKI (EGFR-tyrosine kinase inhibitors), represented by geiftinib and erlotinib, have exhibited signiifcant antiproliferative effects against non-small cell lung cancer (NSCLC) with low toxicity.EGFR gene mutation was discovered to be a predictive biomarker for EGFR-TKI treatment. Although the efifcacy of EGFR-TKI is limited toEGFR wild-type patients, it is still noticeable suggesting that some other mechanisms are responsible for it. The current study is aimed at evaluating the expression of phosphorylated EGFR in advanced NSCLC, investigating its relationship withEGFR mutations and EGFR-TKI efifcacy.Methods:EGFR gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) in 205 stageⅢB-ⅣNSCLC patients. The expressions of phosphorylated tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were detected by immunohistochemistry.Results:The positive expressions of pTyr1068 and pTyr1173 were 80.0% (164/205) and 57.6% (95/165) respectively. None of them were related to clinical pathological characteristics (age, gender, pathological type, smoking status, disease stage).EGFR gene mutation rate was 44.9% (92/205), which was only related to smoking status (P=0.024) compared to other clinical pathological characteristics.EGFR gene mutations were poorly related to pTyr1068 expression (P<0.001) and not related to pTyr1173 expression (P=0.297). The objective response rate (ORR),disease control rate (DCR), and progressive free survival (PFS) of EGFR-TKI treatment in patients withEGFR mutations were 48.3% (43/89), 80.9% (72/89) and 8 months (95%CI: 6.11-11.42) respectively, which were signiifcantly higher than that ofEGFR wild-type patients [ORR=16.2% (17/105,P<0.001); DCR=56.2%(59/105,P<0.001); Median PFS: 2.1 months, (95%CI: 0.89-3.24;P=0.001)]. Superior ORR: DCR and PFS appeared in patients with pTyr1068 positive expression compared to negative [ORR: 37.7% (58/154)vs 5.0% (2/40,P<0.001); DCR: 74.7% (115/154)vs 40.0% (16/40,P<0.001); Median PFS: 7.0 monthsvs 1.2 months,P<0.001)]. Inversely, the patients with pTyr1173 positive expression had lower ORR, DCR and shorter PFS [ORR: 27.8% (25/90)vs 37.9%(25/66,P=0.123); DCR: 64.4% (58/90)vs 83.3% (55/66,P=0.007); Median PFS: 4.8 monthsvs 7.7 months (P=0.016)]. In subgroup ofEGFR wild-type patients, positive expression of pTyr1068 was 69.0% (69/100).EGFR wild-type patients with pTyr1068 positive expression had a prolonged PFS and elevated ORR and DCR compared to negative [median PFS: 3.6 monthsvs 1.2 months (P<0.001); ORR: 23.2%vs 3.2% (P=0.010); DCR: 69.6%vs 35.5% (P=0.001)]. Sixteen patients with pTyr1068 positive expression who responded to EGFR-TKI treatment in this subgroup had a remarkable PFS [median PFS: 15.6 months (95%CI:7.28-23.9)]. Multiple factor analysis showed that the expression of pTyr1068 was an independence predictor factor for EGFR-TKI treatment (OR=0.24, 95%CI: 0.16~0.37,P<0.001). Conclusion:Phosphorylation at Tyr1068 of EGFR might be a potential predictive factor for clinical response and survival of EGFR-TKI treatment in patients with advanced NSCLC, especially inEGFR wild-type patients.

Role of insulin-like growth factor 1 in drug resistance to EGFR-TKIs in non-small cell lung cancer / 第二军医大学学报

Objective: To investigate the expression of insulin-like growth factor 1 (IGF-1) in epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) resistant non-small cell lung cancer (NSCLC) cell lines and patients, and to discuss the relevant clinical significance. Methods: Levels of IGF-1 were measured by ELISA kit in PC9, A549, H1975 cells and sera of EGFR-TKIs treated NSCLC patients; insulin-like growth factor-binding protein (IGFBP) expression was examined by Western blotting analysis and immunocytochemical method. Cell growth of NSCLC cells treated with gefitinib and BMS536924 (antagonist of IGF-1 receptor) was determined by MTT. The clinicopathological characteristics and survival period of 84 patients receiving EGFR-TKIs treatment were collected and their relationship with IGF-1 expression was analyzed. Results: It was found that IGF-1 level in sensitive cell line PC9 was significantly higher than those in EGFR-TKIs resistant cell lines A549 and H1975 (P<0.05), while IGFBP expression was lower than those in A549 and H1975 cells. Addition of BMS536924 of different concentrations significantly promoted the inhibitory effect of gefitinib against growth of A549 and H1975 cells (P<0.05). The patients with disease progression showed higher IGF-1 expression than those without disease progression (P=0.052), while the patients with intrinsic resistance to EGFR-TKIs had significantly higher IGF-1 level than those with acquired resistance (P=0.02). The patients with IGF-1 negative expression had significantly longer survival than those with positive expression (P=0.002). Conclusion: IGF-1 expression is detected in EGFR-TKIs resistant NSCLC cell lines and patients, and antagonist of IGF-1 receptor can restore the sensitivity to EGFR-TKIs. The expression of IGF-1 is also a prognostic factor of NSCLC patients.