Journal Article

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK‐rearranged non–small cell lung cancer

Nishio, Makoto, Baba, Satoko, Fujita, Naoya, Takeuchi, Kengo, Low, Siew‐Kee, Yanagitani, Noriko, Takagi, Satoshi, Sakashita, Takuya, Katayama, Ryohei, Koike, Sumie

2022

Overview

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%‐5% of patients with non–small cell lung cancer (NSCLC) and confers sensitivity to ALK–tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK‐rearranged NSCLC, various additional ALK‐TKIs have been developed. Ceritinib is a second‐generation ALK‐TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first‐generation ALK‐TKI)‐refractory ALK‐rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib‐resistant, echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK–positive H3122 cells and ceritinib‐resistant patient‐derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib‐resistant patient‐derived specimens confirmed that tyrosine‐protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms. For the treatment of ALK rearranged non‐small cell lung cancer, 5 ALK inhibitors approved and prognosis has been markedly improved, but still the emergence of drug resistance is a major obstacle. In this study it was newly found that FGFR3 overexpression and activation mediated ALK‐TKI resistance as a bypass pathway activation mediated resistance.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: ALK kinase / c-Met protein / ceritinib / Cloning / drug resistance / Epidermal growth factor / FDA approval / FGFR3 / Fibroblast growth factor receptor 3 / Fibroblast growth factor receptors / Fibroblasts / Gene amplification / Gene expression / Kinases / Lung cancer / Lymphoma / Mutation / Non-small cell lung carcinoma / Original / Patients / Protein-tyrosine kinase / Small cell lung carcinoma / Statistical analysis / Tumors