Fibroblast growth factor signaling and inhibition in non‐small cell lung cancer and their role in squamous cell tumors

Abstract

With the introduction of targeted agents primarily applicable to non-small cell lung cancer (NSCLC) of adenocarcinoma histology, there is a heightened unmet need in the squamous cell carcinoma population. Targeting the angiogenic fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway is among the strategies being explored in squamous NSCLC; these efforts are supported by growth-promoting effects of FGF signaling in preclinical studies (including interactions with other pathways) and observations suggesting that FGF/FGFR-related aberrations may be more common in squamous versus adenocarcinoma and other histologies. A number of different anti-FGF/FGFR approaches have shown promise in preclinical studies. Clinical trials of two multitargeted tyrosine kinase inhibitors are restricting enrollment to patients with squamous NSCLC: a phase I/II trial of nintedanib added to first-line gemcitabine/cisplatin and a phase II trial of ponatinib for previously treated advanced disease, with the latter requiring not only squamous disease but also a confirmed FGFR kinase amplification or mutation. There are several ongoing clinical trials of multitargeted agents in general NSCLC populations, including but not limited to patients with squamous disease. Other FGF/FGFR-targeted agents are in earlier clinical development. While results are awaited from these clinical investigations in squamous NSCLC and other disease settings, additional research is needed to elucidate the role of FGF/FGFR signaling in the biology of NSCLC of different histologies.

Clinicopathological significance of fibroblast growth factor 1 in non–small cell lung cancer

“…FGFs constitute a superfamily of polypeptides that are involved in multiple biological processes during embryo development, wound healing, and angiogenesis. More recently, several studies indicate that specific FGFs and FGF receptors (FGFRs), such as FGF2, FGF9, FGFR1, FGFR2, and FGFR3, are overexpressed or mutated in NSCLC cells and associated with poor prognosis of patients [6][7][8][9]. Similar with FGF2 and FGF9, FGF1 also is identified as a candidate cancer biomarker [10].…”

La signalisation FGF/FGFR : implication dans l’oncogenèse et perspectives thérapeutiques

“…Le nintédanib, anti-VEGF, PDGFR et FGFR, a montré un intérêt en deuxième ligne dans les cancers bronchiques non à petites cellules, en association au docétaxel [43]. Il est actuellement testé en première ligne dans les cancers bronchiques épidermoïdes, en association avec un traitement par chimiothérapie [41]. Le cédiranib, anti-VEGFR, C-Kit et FGFR, est développé en association avec un inhibiteur de PARP dans le cancer de l'ovaire métastatique [44].…”

Promising Targets and Current Clinical Trials in Metastatic Squamous Cell Lung Cancer

“…FGFR alterations, however, are among the most promising, and have recently been extensively reviewed in Ref. ( 20 ).…”