Advances in the research and clinical application of the third generation EGFR TKIs in the treatment of non-small cell lung cancer / 中国临床药理学与治疗学

Epidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characEpidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characteristics and clinical efficacy of the third-generation EGFR TKIs in the market or in the clinical development. Then this article summarizes the detailed mechanisms behind the acquired drug resistance of third-generation EGFR TKIs，and further expounds the current treatment strategies to overcome the resistance. Collectively, this review could provide more information for the development and clinical application of drugs targeting EGFR.

Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters / 中国肺癌杂志

BACKGROUND@#The incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.@*METHODS@#Between 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.@*RESULTS@#In total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20<cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20>cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P<0.001).@*CONCLUSIONS@#Patients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

Reversal effects and mechanisms of Flavonoids from Tetrastigma hemsleyanum on drug resistance in gefitinib-resistant lung cancer cells / 中国临床药理学与治疗学

AIM: To investigate the sensitization of flavonoids from Tetrastigma hemsleyanum (FTH) on gefitinib (GEF)-resistant lung adenocarcinoma cells. METHODS: The viabilities of A549 and A549/GR cells treated with FTH and GEF were detected by MTT method. The apoptotic rates and cell cycles of A549/GR cells treated with FTH and GEF were detected by Flow cytometry. The anti-tumor effects of flavonoids from FTH and GEF were assayed in A549/GR tumor-bearing mice. The expressions of proteins (PTEN, PI3K, p-PI3K, AKT, p-AKT) were detected by Western blot analysis. RESULTS: Compared with GEF group, FTH significantly enhanced the inhibition of GEF on the proliferation of A549/GR cells (P< 0.05). Combination with FTH and GEF significantly increased the apoptosis of A549/GR cells which were arrested at the G

Application progress of epidermal growth factor receptor tyrosine kinase inhibitors other than lung cancer / 中国药理学通报

Epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKIs) has been mainly used for molecular targeted therapy of advanced non-small cell lung cancer. With the deeper and deeper research of EGFR-TKIs it was found that EGFR and its ligands were involved in the pathogenesis of different human cancers, such as breast cancer and pancreatic cancer. Therefore, the treatment of EGFR-TKIs is no longer limited to advanced non-small cell lung cancer, it also has a good inhibitory effect on malignant tumors such as breast cancer, pancreatic cancer, head and neck cancer, esophageal cancer and cervical cancer. Combination medications are often more effective than medication alone. The article discusses the application research of EGFR-TKIs in the treatment of cancers other than lung cancer and the potential application prospects of EGFR-TKIs combined with other drugs in the treatment of breast cancer, pancreatic cancer and other malignant tumors.

The relationship between EGFR-TKI resistance and PD-L1 expression in the treatment of lung cancer / 中国肿瘤生物治疗杂志

@#[ 摘　要 ] 表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor，EGFR-TKI）的上市， 使治疗EGFR 突变的晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）患者的客观有效率达到79%，取得了显著的抗肿瘤 治疗效果。然而，耐药是EGFR-TKIs 治疗的瓶颈，对耐药机制的研究以及耐药后的治疗策略，成为肺癌治疗的难点和热点问 题。随着免疫治疗的兴起，越来越多的证据发现，PD-L1 不仅与EGFR 基因突变之间存在调节关系，而且PD-L1 表达和EGFR-TKIs 耐药也显示出新的相关性。探究PD-L1 表达与EGFR-TKIs 耐药之间的关系对寻找EGFR-TKIs 耐药后治疗策略具有重要意义。

Characteristics of Epidermal Growth Factor Receptor with Rare Mutations in Non-small Cell Lung Cancer and the Effect of EGFR Tyrosine Kinase Inhibitors on Them / 中国肺癌杂志

BACKGROUND@#Adenocarcinoma is the most common type of lung cancer. It has been clinically evaluated that therapiestargeting against the epidermal growth factor receptor (EGFR) as the clinical standard first-line treatment. The response and outcome of EGFR-tyrosine kinase inhibitors (TKIs) in patients harboring common mutations in EGFR kinase domain (deletion in exon19 and L858R in exon 21) has been well demonstrated, but not in rare or complex mutations.@*METHODS@#A total of 150 patients that harbored rare or complex mutations in EGFR diagnosed by histopathology were included in this retrospective study. The clinical-pathological characteristics of all 150 patients as well as the response and progression-free survival (PFS) in 48 patients that received EGFR-TKIs in first/second/third line treatments weredescribed and analyzed.@*RESULTS@#Patients were divided into four groups based on the mutation types: single G719X point mutation in exon 18 (n=46, 30.7%), single L861Q point mutation in exon 21 (n=45, 30.0%), other single rare mutation (n=14, 9.3%) and complex mutations (n=45, 30.0%). The result indicated thatthere was no correlation of EGFR mutation typeswith other parameters such as gender, age, clinical stage, pathology and smoking history. For the 48 patients that received EGFR-TKIs treatment, there were no significant differencesamong 4 groups in terms of objective response rate (ORR) and disease control rate (DCR) (54.5% vs 30.0% vs 0.0% vs 35.7%, χ²=3.200, P=0.34; 90.9% vs 85.0% vs 66.7% vs 92.9%, χ²=2.162, P=0.59). The median progress-free survival (mPFS) was 11.0 months (95%CI: 4.4-17.6), and in each group of different EGFR mutation types are 15.8 months (95%CI: 9.5-22.2), 8.0 months (95%CI: 5.1-11.0), 4.9 months (95%CI: 1.4-8.4) and 23.1 months (95%CI: 15.8-30.4)(χ²=7.876, P=0.049).@*CONCLUSIONS@#The efficiency of targeting EGFR-TKIs on different types of rare or complex mutations was heterogeneous. The PFS may be better in patients that harbored complex mutations than those with single rare mutations. Further studies with larger sample size are necessary. Moreover, to discover novel therapeutic targets and develop new drugs are imminentfor those patientswith no response to the existing treatments.

Nrf2 and Keap1 Abnormalities in 104 Lung Adenocarcinoma Cases and Association with Clinicopathologic Features / 中国肺癌杂志

BACKGROUND@#There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or Kelch-like ECH-associated protein 1 (Keap1) in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different "driver gene" is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients.@*METHODS@#Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type.@*RESULTS@#The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P0.05). The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05). The progression -free survival (PFS) and overall survival (OS) of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05). Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05).@*CONCLUSIONS@#The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.

Research Progress of the Role of EMT in EGFR-TKIs Resistance of Non-small Cell Lung Cancer / 中国肺癌杂志

Lung cancer is the one of the malignant tumor of the highest morbidity and mortality over the world, and non-small cell lung cancer (NSCLC) makes up about 80%. Nowadays, molecular targeted therapy has been the first-line treatment for NSCLC. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are increasingly used in the clinical treatment, but the EGFR-TKIs acquired resistance becomes the bottleneck of continuation of EGFR-TKIs therapy. Epithelial-mesenchymal transition (EMT) is a biological phenomenon in which epithelial cells are transformed into mesenchymal cells. EMT promoted metastasis, invasion of lung cancer and conferred characteristic of stem cell on cancer cells. Meanwhile, EMT is one of an important cause of EGFR-TKIs resistance in NSCLC. The recent studies have found that resistant cells restored the sensitivity to EGFR-TKIs by reversing EMT which suggested that the target of EMT may contribute to inhibit or even reverse the resistance of EGFR-TKIs. Here we make a review about research progress of EMT in EGFR-TKIs resistance in NSCLC.
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Advances in pulmonary fibrosis caused by thoracic radiotherapy combined with EGFR-TKIs / 实用肿瘤学杂志

Thoracic radiotherapy is an important means of local treatment for non -small cell lung cancer (NSCLC).Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)have the effect of systemic therapy.Studies have shown that NSCLC patients with EGFR exons 19,21 mutation have a synergistic effect in the combination therapy .Radiotherapy activates EGFR signaling pathway ,inducing cell proliferation and DNA damage repair,leading to radiation resistance .Therefore,EGFR-TKIs have the effect in increasing radiosensitivity .Lung injury is one of the most common side effects when the two therapies combined .Studies suggest that radiotherapy combined with EGFR-TKIs may have conflicting functions in the development of pulmonary fibrosis ,the discrep-ancy between these studies may depend on the differences in the experimental systems ,the differences in pulmo-nary fibrosis models,as well as the differences between different species and individuals .Therefore,a more com-plete understanding of the etiology for pulmonary fibrosis is necessary to the development of improved treatments .

The role of epithelial-mesenchymal transition and insulin-like growth factor i receptor in acquired resistance to epidermal growth factor-tyrosine kinase inhibitors in non-small cell lung cancer / 肿瘤

Objective: To investigate the role of EMT (epithelial-mesenchymal transition) and IGF- 1R (insulin-like growth factor I receptor) in acquired resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in NSCLC (non-small cell lung cancer). Methods: The EGFR mutant human lung adenocarcinoma PC-9 cell line and the EGFR wild-type H460 cell line were used to generate gefitinib-resistant PC-9 cells (named as PC-9/ZD cells) and erlotinib-resistant cells (named as H460/ER cells), respectively. MTT assay was used to measure the cell proliferation of PC9, PC-9/ZD, H460 and H460/ER cells. Wound-healing assay and Transwell assay were used to determine the migration and invasion capabilities of the cells. The protein and mRNA expressions of E-cadherin, vimentin, EGFR, ERK (extracellular signal-regulated kinase), AKT (protein kinase B) and IGF-1R were determined by Western blotting and RT-PCR (reverse transcription PCR), respectively. Results: Both PC-9/ZD and H460/ER cells acquired resistance to EGFR-TKIs which was to say that the sensitivities to gefitinib and erlotinib in PC-9/ ZD and H460/ER cells were significantly decreased, respectively (P < 0.05). Compared with PC-9 and H460 cells, the PC-9/ZD and H460/ER cells displayed mesenchymal phenotypes, and their capabilities of invasion and migration were enhanced (P < 0.05). The expression of mesenchymal cell marker vimentin was increased in both PC-9/ZD and H460/ER cells (P < 0.05), and the expression of E-cadherin was decreased in PC-9/ZD cells (P < 0.05). The expressions of IGF-1R and its phosphorylated form in both PC-9/ZD and H460/ER cells were significantly increased (P < 0.05) as compared with those in the PC-9 and H460 cells, accompanied by up-regulation of phosphorylation levels of AKT and ERK (P < 0.05). No significant difference was found in phosphorylation level of EGFR between PC-9 and PC-9/ZD cells (P < 0.05), while the phosphorylation level of EGFR was significantly decreased in H460/ER cells as compared with that in H460 cells (P < 0.05). Conclusion: The EMT in EGFR mutant gefitinib-resistant PC-9/ZD cells and the EGFR wild-type erlotinib-resistant H460/ER cells was accompanied by a increase in protein expression of IGF-1R, which suggests EMT and IGF-1R signal transduction may play an important role in acquired resistance to EGFR-TKIs in NSCLC cells. Copyright © 2013 by TUMOR.