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 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.

• Authors: Sana Raoof, Iain J Mulford, Heidie Frisco-Cabanos, Varuna Nangia, Daria Timonina, Emma Labrot, Nafeeza Hafeez, Samantha J Bilton, Yotam Drier, Fei Ji, Max Greenberg, August Williams, Krystina Kattermann, Leah Damon, Sosathya Sovath, Daniel P Rakiec, Joshua M Korn, David A Ruddy, Cyril H Benes, Peter S Hammerman, Zofia Piotrowska, Lecia V Sequist, Matthew J Niederst, Jordi Barretina, Jeffrey A Engelman, Aaron N Hata
• Journal: Oncogene (Oncogene) Vol. 38 Issue 37 Pg. 6399-6413 (09 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 31324888 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Protein Kinase Inhibitors
• RNA, Small Interfering
• EGFR protein, human
• ErbB Receptors
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• ErbB Receptors (genetics, physiology)
• Female
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• RNA, Small Interfering (pharmacology)
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, genetics)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays