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

Abstract

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.

Role of human epidermal growth factor receptor 3 in treatment resistance of anaplastic lymphoma kinase translocated non-small cell lung cancer

“…Other described bypass resistance mechanisms include activation of FGFR2&3 and cMET. 29 Interestingly, previous studies have identified and receptor tyrosine kinases (RTK), such as FGFR2, can act as an upstream activator of ERBB3. 30 In addition, metabolic reprogramming of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) via STAT3 has recently been linked to ALK TKI resistance.…”

Targeting FGFRs by pemigatinib induces G1 phase cell cycle arrest, cellular stress and upregulation of tumor suppressor microRNAs

“…Unfortunately, the onset of acquired resistance is a common event and dramatically Pace et al Journal of Translational Medicine (2023) 21:626 hampers therapeutic efficacy [63]. FGFR signaling pathways have been described as molecular mechanisms for acquired resistance to TKIs targeting other tyrosine kinase receptors, such as EGFR, c-Met, ALK and CDK4/6 [64][65][66]. Although functional studies are needed, the evidence that pemigatinib treatment can modulate other TKI targets reinforces the biological rationale for combinatorial strategies to overcome TKI resistance and improve clinical benefit.…”

High expression of FGFR3 predicts a better prognosis for patients with non-small cell lung cancer in a Chinese population

“…FGFR3 spans 16.5 kb with 18 introns and 19 exons and is situated on chromosome 4p16.3. FGFR3 is a member of the FGFR family and has been found to regulate cell growth, cell differentiation, and migration ( 16 , 17 ). FGFR3 is involved in a variety of biological processes including cell proliferation, differentiation, migration, angiogenesis, and apoptosis.…”

“…FGFR3 spans 16.5 kb with 18 introns and 19 exons and is situated on chromosome 4p16.3. FGFR3 is a member of the FGFR family and has been found to regulate cell growth, cell differentiation, and migration (16,17).…”