Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer

Abstract

Evolved resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR T790M mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified FGFR1 as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data has not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug tolerant cells over long time periods, preventing the development Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Cycling cancer persister cells arise from lineages with distinct transcriptional and metabolic programs

“…To identify cellular programs that are associated with the ability of persisters to cycle, we searched for gene signatures that are differentially expressed between the persister subpopulations, but are cell cycle independent. In line with previous reports (Hangauer et al, 2017;Raoof et al, 2019), epithelial-mesenchymal transition (EMT) genes and GPX4, a hydroperoxidase that protects cells against membrane lipid peroxidation, were induced by the EGFR inhibitor; however, the levels of induction were similar in both the cycling and non-cycling persister populations ( Fig. S3a, b), suggesting that these programs are not underlying the ability of persisters to cycle.…”

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

“…These observations suggest that the FGFR1-associated kinase switch occurs as a consequence of EMT and not the other way around. Nevertheless, targeted inhibition of FGFR may be a viable strategy to overcome resistance to EGFR TKIs linked to EMT (Raoof et al, 2019).…”

Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy

“…Herein, we demonstrate that FGFR1 can act as a major driver of tumor recurrence following onset of HER2 discordance and acquisition of resistance to T-DM1 and other ErbB-targeted therapies. Previous studies from our lab and others suggest that FGFR can act as an bypass mechanism to facilitate resistance to ErbB kinase inhibitors (17,18,20,38). Furthermore, FGFR signaling has also been identified as a mechanism of resistance to endocrine therapies in breast and prostate cancer (19,39).…”

“…The reasons for this are potentially numerous, but a possible explanation is the inducible nature of FGFR expression. In particular, FGFR1, FGFR3 and FGF2 expression are dramatically upregulated during the processes of EMT (17,20). While the mechanisms of FGFR1 upregulation during EMT remain to be fully elucidated, this event presents a functional and targetable link between EMT and the acquisition of drug resistance.…”

“…FGFR1 can also undergo gene amplification and translocation, and elevated expression of FGFR1 is associated with decreased clinical outcomes of breast cancer patients (14) (15,16). Work from our lab and others suggest that upregulation of FGFRs and FGF ligands can serve as resistance mechanisms for tumor cells that were originally sensitive to ErbB and endocrine-targeted therapies (16)(17)(18)(19)(20). In addition to enhanced expression of the receptor, our recent studies demonstrate that the processes involved in EMT work en masse to support FGFR signaling through diminution of E-cadherin and enhanced interaction with integrins (21).…”