Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial–mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.

Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

“…Additionally, H1975 (L858R/T790M) and H1650 (del E746_A750/ PTEN null) cells exhibit inherent resistance [ 18 ]. Models using such cell lines are considered adequate for studying resistance to EGFR TKIs [ 19 ] because many of their resistance mechanisms recapitulate those identified in studies of clinical specimens obtained from TKI-refractory patients.…”

In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies

“…For example, RNAi and CRISPR screens have been widely successful in identifying often unexpected partners for combination therapies 24 , 25 , 26 ; however, the time frame of these approaches biases them toward identifying and assessing secondary drug targets that will limit intrinsic, but not acquired, resistance. Further, those studies that do assess acquired resistance in situ are limited to the assessment of a few cell lines established by dose escalation over multiple months (reviewed in 27 ) (e.g., 28 , 29 , 30 , 31 , 32 ) rather than determining the extent to which inhibiting a secondary drug target can delay the onset of resistance. Therefore, a framework of pre-clinical experiments to assess initial efficacy combined with extended in vitro approaches such as 6- to 16-week proliferation outgrowth assays 33 , 34 and time-to-progression (TTP) assays 26 can provide robust evidence for proposing effective and rational combination therapies that is accessible and scalable.…”

In situ modeling of acquired resistance to RTK/RAS pathway targeted therapies

“…For example, RNAi and CRISPR screens have been widely successful in identifying novel and often unexpected partners for combination therapies ( 9–11 ), however, the timeframe of these approaches biases them toward identifying and assessing secondary drug targets that will limit intrinsic, but not acquired, resistance. Further, those studies that do assess acquired resistance in situ are limited to the assessment of a few cell lines established by dose-escalation over multiple months (reviewed in ( 12 )) (e.g. ( 13–17 )) rather than determining the extent to which inhibiting a secondary drug target can delay the onset of resistance.…”