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]

scholarly journals A Novel Molecular Target in EGFR-Mutant Non-Small Cell Lung Cancer Treated With a Combination of Osimertinib and Pemetrexed

2021 ◽  
Author(s):  
Natsuki Takano ◽  
Masahiro Seike ◽  
Teppei Sugano ◽  
Kuniko Matsuda ◽  
Kakeru Hisakane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Egfr Tki

Abstract Overcoming acquired resistance to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is currently an important clinical issue in treating EGFR-mutant non-small cell lung cancer (NSCLC) patients. EGFR-TKI may synergize with chemotherapy and offer novel treatment strategies for overcoming acquired resistance. Here, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms. Gene expression microarrays were used to assess gene expression on exposure to osimertinib in the presence or absence of pemetrexed and we established cell lines resistant to osimertinib as well as those resistant to osimertinib+pemetrexed in order to explore mechanisms of resistance. Osimertinib+pemetrexed treatment significantly delayed the emergence of resistance relative to monotherapy in vitro and in vivo. Microarray analysis revealed significantly downregulated expression of the anti-apoptotic gene PLK1 in cells treated with osimertinib+pemetrexed. Consistent with this, cell lines resistant to osimertinib or to osimertinib+pemetrexed, exhibited overexpression of PLK1. Accordingly, PLK1 inhibition by siRNA or PLK1 inhibitor volasertib inhibited proliferation by inducing apoptosis in these resistant cell lines. Blocking PLK1 contributes to mediating the synergistic antiproliferative effect of osimertinib+pemetrexed in EGFR-mutant NSCLC cells. PLK1 overexpression may be a critical mechanism responsible for the acquired resistance of such mutants to osimertinib+pemetrexed.

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Bo Mi Ku ◽  
Jae Yeong Heo ◽  
Jinchul Kim ◽  
Jong-Mu Sun ◽  
Se-Hoon Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Thus, development of effective strategies to overcome resistance to EGFR-TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR-TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR-TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR-TKIs synergistically decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR-TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR-TKIs by overcoming acquired resistance.

mPGES-1 as a new target to overcome acquired resistance to gefitinib in non-small cell lung cancer cell lines

2019 ◽  
Vol 143 ◽  
pp. 106344 ◽  
Author(s):  
Erika Terzuoli ◽  
Filomena Costanza ◽  
Valerio Ciccone ◽  
Marina Ziche ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Cancer Cell Lines ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung
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