Abstract
The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms.
Highlights
The discovery of oncogenic driver genes has helped identify druggable targets and the subsequent development of new therapies using small molecule tyrosine kinase inhibitors (TKI) for a broad range of cancers
Novel Fibroblast growth factor receptor 2 (FGFR2) gene alterations detected in solid tumors We first studied the tumor of a 37-year-old male never smoker with advanced non–small cell lung cancer (NSCLC)
Aberrant FGFR signaling has been implicated in the development of several cancer types, including FGFR1 amplification in lung squamous cell carcinoma [7, 21], FGFR3 mutations in urothelial carcinomas [22], and recently reported fusions of FGFR family kinases with TACC or other genes in several cancer types [9, 11, 23, 24]
Summary
The discovery of oncogenic driver genes has helped identify druggable targets and the subsequent development of new therapies using small molecule tyrosine kinase inhibitors (TKI) for a broad range of cancers. Detection of epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements in non–small cell lung cancer (NSCLC) is currently standard of care, leading to dramatically improved outcomes in patients with these genetic alterations when treated with an EGFR or ALK TKIs, respectively, as compared with systemic chemotherapy [1, 2]. A number of new potentially targetable oncogenic gene alterations have been further characterized in recent years [3]. Given the fact that cancer is the leading cause of death worldwide and accounts for 8.2 million deaths annually [4], identifying even a small subpopulation of patients who might.
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