RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1 -Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

• Published in: Molecular cancer therapeutics Vol. 17; no. 7; pp. 1526 - 1539
• Main Authors: Bockorny, Bruno, Rusan, Maria, Chen, Wankun, Liao, Rachel G, Li, Yvonne, Piccioni, Federica, Wang, Jun, Tan, Li, Thorner, Aaron R, Li, Tianxia, Zhang, Yanxi, Miao, Changhong, Ovesen, Therese, Shapiro, Geoffrey I, Kwiatkowski, David J, Gray, Nathanael S, Meyerson, Matthew, Hammerman, Peter S, Bass, Adam J
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.07.2018
• Subjects: Activation; Animals; Axl protein; Bladder; Cancer; Cholangiocarcinoma; Chronic exposure; Clinical trials; Cloning; Drug Resistance, Neoplasm - genetics; Extracellular signal-regulated kinase; Fibroblast growth factor receptor 1; Fibroblast growth factor receptors; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genomes; Head & neck cancer; Humans; Inhibition; Inhibitors; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MAP kinase; MAP Kinase Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase Kinase 1 - genetics; Medical research; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - genetics; Mutation; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Signal Transduction - drug effects; Squamous cell carcinoma; Therapeutic applications; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0464

The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a -dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS-MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. .