Targeting FGFR Signaling in Cancer

Abstract

The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents. Clin Cancer Res; 21(12); 2684-94. Ó2015 AACR.

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

“…Preclinical or clinical trials evaluating the antitumor effect of FGFR inhibitors are under current, most of them concerning tyrosine kinase inhibitors targeting FGFR as single agents or in combination with other drugs (for review, ref. 44) or for some of them with radiotherapy (45). For our part, we recently reported preclinical evidence that targeting FGFR1 in association with radiotherapy could overcome the radioresistance of glioblastoma cells, sustaining the hypothesis that FGFR inhibitors might be not used as single agents but in combination with radiotherapy (13) in high-grade glioma treatment.…”

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

“…Currently, numerous FGFR inhibitors including PD173074, dovitinib, and ponatinib that block the tyrosine kinase domain of FGFRs are undergoing clinical trials for cancer treatment (37)(38)(39). Although these drugs exhibit substantial clinical responses, nonsynonymous mutations have been identified among the FGFRs.…”

Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

“…In contrast, constitutive ligand-independent and aberrant liganddependent FGFR signaling have been described in a large variety of solid tumors, including non-small cell lung, breast, bladder, endometrial, gastric, and colon cancer, as well as certain hematological malignancies. Aberrant pathway activation is believed to be a key growth promoting mechanism for these malignancies (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Further support of this concept is highlighted by the presence of activating FGFR gene alterations, including point mutations and gene rearrangements, in multiple tumor types, suggesting that deregulated proliferation of certain tumors is driven by these oncogenic events (7,17).…”