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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
Sana Raoof1, Iain J Mulford2, Heidie Frisco-Cabanos1
1Massachusetts General Hospital (MGH) Cancer Center, Charlestown, MA, USA.
Abstract:
Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (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 EGFRT790M 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 fibroblast growth factor receptor 1 (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 have 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 of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.
Insights
Targeting fibroblast growth factor receptor 1 (FGFR1) alongside epidermal growth factor receptor (EGFR) inhibitors may prevent resistance in non-small-cell lung cancer. This dual blockade inhibits drug-tolerant cells, preventing acquired resistance to EGFR tyrosine kinase inhibitors (TKIs).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Acquired resistance to tyrosine kinase inhibitors (TKIs) is a significant clinical hurdle in EGFR-mutant non-small-cell lung cancer (NSCLC).
- Mechanisms of resistance include genetic alterations and epigenetic changes, such as epithelial-to-mesenchymal transition (EMT), which generates drug-tolerant persister cells.
- Existing therapies target fully resistant cells, but strategies to prevent persister cell emergence are lacking.
Purpose of the Study:
- To identify therapeutic targets that promote the survival of mesenchymal EGFR-mutant cancer cells, serving as surrogates for persister populations.
- To investigate the role of fibroblast growth factor receptor 1 (FGFR1) signaling in EGFR TKI resistance.
- To evaluate the efficacy of combined EGFR and FGFR inhibition in preventing and overcoming acquired resistance.
Main Methods:
- Whole-genome CRISPR screening was employed using mesenchymal cell lines derived from EGFR TKI-resistant patient biopsies.
- In vitro and in vivo models were utilized to assess the impact of combined EGFR and FGFR inhibition on drug-tolerant cells.
- The study focused on preventing the development of fully resistant cancers.
Main Results:
- Whole-genome CRISPR screening identified FGFR1 as a key survival target in mesenchymal EGFR-mutant cancers.
- Combining EGFR and FGFR inhibitors effectively suppressed the survival and expansion of EGFR-mutant drug-tolerant cells over extended periods.
- This dual blockade prevented the development of fully resistant cancers in both in vitro and in vivo settings.
Conclusions:
- Dual blockade of EGFR and FGFR signaling presents a promising strategy for preventing and overcoming EMT-associated acquired resistance in EGFR-mutated NSCLC.
- The findings provide a strong rationale for clinical trials investigating combined EGFR and FGFR inhibition in this patient population.
- Targeting FGFR1 is crucial for inhibiting persister cell survival and preventing TKI resistance evolution.
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