Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer

2019 ◽  
Vol 21 (10) ◽  
pp. 1287-1301 ◽  
Author(s):  
J. Gao ◽  
H.-R. Li ◽  
C. Jin ◽  
J.-H. Jiang ◽  
J.-Y. Ding
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tki

scholarly journals Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2596
Author(s):  
Wonjun Ji ◽  
Yun Jung Choi ◽  
Myoung-Hee Kang ◽  
Ki Jung Sung ◽  
Dong Ha Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tki ◽  
Egfr Tkis

Epithelial to mesenchymal transition (EMT) is associated with resistance during EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Here, we investigated whether EMT is associated with acquired resistance to 3rd generation EGFR-TKIs, and we explored the effects of cyclin-dependent kinase 7 (CDK7) inhibitors on EMT-mediated EGFR-TKIs resistance in non-small cell lung cancer (NSCLC). We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. The two resistant cell lines showed phenotypic changes to a spindle-cell shape, had a reduction of epithelial marker proteins, an induction of vimentin expression, and enhanced cellular mobility. The EMT-related resistant cells had higher sensitivity to THZ1 than the parental cells, although THZ1 treatment did not inhibit EGFR activity. This phenomenon was also observed in TGF-β1 induced EMT cell lines. THZ1 treatment induced G2/M cell cycle arrest and apoptosis in all of the cell lines. In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.

EGFR-TKI rechallenged treatment combined with apatinib in non-small cell lung cancer with EGFR-TKI resistance.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20529-e20529 ◽  
Author(s):  
Li Liang ◽  
Fang Li ◽  
Baoshan Cao ◽  
Zhaohui Zhang ◽  
Xiang Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3 ◽  
Egfr Tki ◽  
Egfr Tkis

e20529 Background: Acquired resistance to EGFR-TKIs frequently occurs in non-small cell lung cancer (NSCLC) patients (pts) with sensitizing EGFR mutations. EGFR-TKIs rechallenged therapy is one of the recommended strategies. This study aimed to explore the efficacy and safety of EGFR-TKI combined with apatinib (a TKI against VEGFR-2) in EGFR-TKIs resistant pts. Methods: From Aug 2015 to Nov 2016, we retrospectively screened 16 NSCLC pts who acquired resistance to the EGFR-TKI therapy and chose apatinib plus EGFR-TKI as the second-line treatment in our hospital. All pts signed informed consent before treatment. Results: Pts characteristics and efficacy are shown in the table below. Two pts discontinued on the 4th and 10th day due to side effects, respectively, and thus were excluded from short efficacy analysis. No CR, 4 PR and 10 SD were confirmed, resulting in an objective response rate of 28.6% and a disease control rate of 100%, respectively. At the cut-off date on Feb 7, 2017, 6 pts were still being treated. The median progression-free survival was 4.60 months (95%CI, 2.23–12.52 months). The main adverse events were hypertension, hand-foot skin reaction (HFSR) and diarrhea. Five (31.3%) grade 3 hypertension, 1 (6.3%) grade 3 HFSR and 1 (6.3%) grade 3 diarrhea were observed. Conclusions: EGFR-TKI combined with apatinib may stand for a new option for NSCLC pts with acquired EGFR-TKIs resistance. [Table: see text]

MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer

Lung Cancer ◽  
2014 ◽  
Vol 83 (2) ◽  
pp. 146-153 ◽  
Author(s):  
Bing Li ◽  
Shengxiang Ren ◽  
Xuefei Li ◽  
Yongsheng Wang ◽  
David Garfield ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tki

scholarly journals Reversal of Acquired Resistance to EGFR–TKI in T790M-negative Patients With Non–small-cell Lung Cancer Using Anlotinib

2021 ◽  
Author(s):  
Chen Zhang ◽  
Honggang Cao ◽  
Shidai Jin ◽  
Wen Gao ◽  
Chenjun Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Combination Therapy ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Effect ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tki

Abstract Background: Treatment options for epidermal growth factor receptor (EGFR) T790M-negative patients with non–small-cell lung cancer (NSCLC) and acquired resistance (AR) to EGFR–tyrosine kinase inhibitor (EGFR–TKI) are limited. The efficacy of EGFR–TKI and anti-angiogenic drug combination therapy in these patients is known. We investigated the effectiveness of EGFR–TKI+anlotinib combination therapy in patients with T790M-negative NSCLC. Method: We evaluated the antitumor effects of gefitinib combined with anlotinib in gefitinib-resistant lung adenocarcinoma cells. We also investigated the treatment effect and absence of adverse events of EGFR–TKI+anlotinib therapy in 22 T790M-negative patients after EGFR–TKI treatment failure between January 2018 and August 2020. Results: Anlotinib reversed gefitinib resistance in the gefitinib-resistant cell line, PC9/GR, by enhancing anti-proliferative and pro-apoptotic effects of gefitinib. The gefitinib+anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI+anlotinib therapy exhibited an objective response rate of 18.2% and a disease control rate of 95.5%. The median progression-free survival (PFS) was 11.53 ± 1.94 months, whereas the median overall survival was not reached. The median PFS was longer in patients exhibiting gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (8.60 ± 5.39 months, p = 0.041). One Grade 3 adverse event was noted (diarrhea, n = 2, 9.1%), and Grade 4 or 5 adverse events were absent.Conclusion: EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and excellent treatment effect in T790M-negative NSCLC patients after AR.

scholarly journals Modern vector in treatment of patients with lung cancer: tyrosine kinase inhibitors in epidermal growth factor receptor mutations (literature review)

2021 ◽  
Vol 26 (2) ◽  
pp. 4-11
Author(s):  
O.M. Smorodska ◽  
Yu.V. Moskalenko ◽  
I.O. Vynnychenko ◽  
O.I. Vynnychenko ◽  
V.V. Kostuchenko
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Egfr Tki

Tumor molecular profiling in patients with non-small cell lung cancer (NSCLC) is used to identify driver mutations, which lead to premature carcinogenesis in more than 80% of adenocarcinoma cases, including epidermal growth factor receptor (EGFR) mutations. Identification of specific somatic aberrations allows to personalize treatment. Personalization of treatment resulted in improvement of NSCLC outcomes. The aim of our study was to consider scientific data on modern concepts of treatment of patients with non-small cell lung cancer with previously detected oncogenic mutations, especially EGFR mutation. In our study we analyzed scientific papers and data of international scientific literature on the problem of lung cancer treatment. Methods used: scientific research, analytical and generalizing. Different drugs are used in treatment of lung cancer. Choice of treatment scheme depends on type and presence of mutations. Patients with advanced non-small-cell lung cancer and detected mutation in the EGFR can be treated with tyrosine kinase inhibitors (TKIs). Nowadays three first generation drugs are recommended by FDA: afatinib, erlotinib, gefitinib. They showed good clinical benefit. Most patients with metastatic NSCLC typically show disease progression after approximately 9 to 13 months of erlotinib, gefitinib, or afatinib therapy. The first and only commercially available third-generation EGFR TKI is оsimertinib - an oral drug, which selectively inhibits both EGFR-TKI and EGFR T790M resistance mutations. Nowadays scientists are in active investigation of mechanisms of acquired resistance to TKIs, but little is known yet. Clinical success can be observed in patients who were treated with TKIs. EGFR T790M is a mutation that leads to acquired resistance to EGFR TKI therapy. Its incidence is approximately 60% after disease progression on TKI drugs (erlotinib, gefitinib, or aphatinib). Third-generation EGFR TKIs demonstrate high efficacy, but acquired resistance development cannot be avoided. Mechanisms of acquired resistance to these agents are still investigated.

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