Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib

Liu, Yutao; Li, Yan; Ou, Qiuxiang; Wu, Xue; Wang, Xiaonan; Shao, Yang; Jin, Ying

doi:10.1016/j.lungcan.2018.01.015

Cited by 56 publications

(46 citation statements)

References 11 publications

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“…87 Similarly, preclinical studies have shown that the secondary EGFR L718V mutation confers resistance to osimertinib but retains sensitivity to the EGFR inhibitor afatinib. 95 Considering that resistance to osimertinib usually involves multiple mechanisms, such as the activation of alternative cellular pathways or aberrant downstream signalling, osimertinib-based combination therapies are being extensively investigated ( Table 1). The combination of osimertinib with pemetrexed or cisplatin has been investigated in EGFR-mutant NSCLC preclinical models.…”

Section: Pi3k Pathway Activationmentioning

confidence: 99%

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Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

et al. 2019

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Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution. This review summarises the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation, as well as discussing the current evidence regarding potential new approaches to counteract osimertinib resistance.

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Section: Pi3k Pathway Activationmentioning

confidence: 99%

“… 87 Similarly, preclinical studies have shown that the secondary EGFR L718V mutation confers resistance to osimertinib but retains sensitivity to the EGFR inhibitor afatinib. 95 …”

Section: Therapeutic Strategies To Overcome Osimertinib Resistancementioning

confidence: 99%

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

et al. 2019

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“…Resistance can occur by selection of pre-existing drug-resistant subpopulations or by adaptation of originally drug-sensitive cells to anti-cancer therapies. Both mechanisms have been shown to be represented in drug-adapted cancer cell lines [52,[66][67][68][69][70][90][91][92][93][94][95][96][97][98][99][100][101] .…”

Section: Multiple Resistance Models Are Needed To Reflect the Heterogmentioning

confidence: 99%

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Michaelis¹,

Wass²,

Činátl³

2019

CDR

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Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

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“…Acquired resistance to EGFR-TKIs such as gefitinib and erlotinib is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Acquired EGFR mutation (T790M) can lead to resistance to gefitinib treatment (14). EGFR mutation (L858R/L718V) confers resistance to osimertinib.…”

Section: Introductionmentioning

confidence: 99%

“…EGFR mutation (L858R/L718V) confers resistance to osimertinib. However, it retains sensitivity to second generation TKI afatinib (14). Erlotinib-resistance is associated with EGFR kinase domain (15).…”

Section: Introductionmentioning

confidence: 99%

CAGE Binds to Beclin1, Regulates Autophagic Flux and CAGE-Derived Peptide Confers Sensitivity to Anti-cancer Drugs in Non-small Cell Lung Cancer Cells

et al. 2018

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The objective of this study was to determine the role of CAGE, a cancer/testis antigen, in resistance of non-small cell lung cancers to anti-cancer drugs. Erlotinib-resistant PC-9 cells (PC-9/ER) with EGFR mutations (ex 19 del + T790M of EGFR), showed higher level of autophagic flux than parental sensitive PC-9 cells. Erlotinib and osimertinib increased autophagic flux and induced the binding of CAGE to Beclin1 in PC-9 cells. The inhibition or induction of autophagy regulated the binding of CAGE to Beclin1 and the responses to anti-cancer drugs. CAGE showed binding to HER2 while HER2 was necessary for binding of CAGE to Beclin1. CAGE was responsible for high level of autophagic flux and resistance to anti-cancer drugs in PC-9/ER cells. A peptide corresponding to the DEAD box domain of CAGE, 266AQTGTGKT273, enhanced the sensitivity of PC-9/ER cells to erlotinib and osimertinib, inhibited the binding of CAGE to Beclin1 and regulated autophagic flux in PC-9/ER cells. Mutant CAGE-derived peptide 266AQTGTGAT273 or 266AQTGTGKA273 did not affect autophagic flux or the binding of CAGE to Beclin1. AQTGTGKT peptide showed binding to CAGE, but not to Beclin1. FITC-AQTGTGKT peptide showed co-localization with CAGE. AQTGTGKT peptide decreased tumorigenic potentials of PC-9/ER and H1975 cells, non-small cell lung cancer (NSCLC) cells with EGFR mutation (L885R/T790M), by inhibiting autophagic fluxand inhibiting the binding of CAGE to Beclin1. AQTGTGKT peptide also enhanced the sensitivity of H1975 cells to anti-cancer drugs. AQTGTGKT peptide showed tumor homing potential based on ex vivo homing assays of xenograft of H1975 cells. AQTGTGKT peptide restored expression levels of miR-143-3p and miR-373-5p, decreased autophagic flux and conferred sensitivity to anti-cancer drugs. These results present evidence that combination of anti-cancer drug with CAGE-derived peptide could overcome resistance of non-small cell lung cancers to anti-cancer drugs.

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Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib

Cited by 56 publications

References 11 publications

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Drug-adapted cancer cell lines as preclinical models of acquired resistance

CAGE Binds to Beclin1, Regulates Autophagic Flux and CAGE-Derived Peptide Confers Sensitivity to Anti-cancer Drugs in Non-small Cell Lung Cancer Cells

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