FGFR Alterations Emerge as Enticing Target in Multiple Tumor Types

Gina Battaglia, PhD
Published: Friday, Mar 29, 2019
Aberrations in fibroblast growth factor receptor (FGFR) signaling are an emerging focus for targeted therapy across multiple types of cancer, particularly urothelial carcinoma, gastric cancer, and intrahepatic cholangiocarcinoma. However, recent research findings demonstrating variability in the efficacy of FGFR-targeted therapies across different FGFR aberrations emphasize the importance of patient selection for clinical trials and further studies of combination regimens to be used with FGFR inhibitors.

The fibroblast growth factor (FGF)/FGFR pathway is a tyrosine kinase signaling network involved in cell proliferation, differentiation, apoptosis, and migration.1-4 The FGF family includes 22 known ligands that bind to members of the FGFR family, which consists of 4 highly conserved transmembrane receptor tyrosine kinases (FGFR1/2/3/4) and 1 FGF-binding receptor that does not have an intracellular kinase domain (FGFR5 or FGFRL1). Binding of FGF ligands to FGFRs leads to dimerization and regulation of a cascade of downstream signaling pathways, including MAPK, STAT, PI3K/AKT, and DAG-PKC and IP3-Ca2+ pathways (Figure 1).4-7

Figure 1. FGFR Pathway Activity Implicated in Oncogenic Signaling7

Figure 1. FGFR Pathways Activity Implicated in Oncogenic Signaling7 Aberrations in FGFR represent a key target for cancer therapy for a subgroup of certain types of malignancies. A study using next-generation sequencing (NGS) on samples from about 5000 patients with various cancers showed FGFR aberrations in 7.1% (Figure 2). Amplifications in FGFR accounted for the majority of these aberrations (66%), followed by activating mutations (26%) and gene rearrangements or fusions (8%).8 Overall, aberrations in FGFR1/2/3/4 were most frequently found in urothelial (31.7%), breast (17.4%), endometrial (11.3%), and ovarian cancers (8.6%).8

Study findings show a variation in the type of aberration and the specific gene within the family across cancer types. Amplification accounts for approximately 89% of all FGFR1 aberrations8 and has been demonstrated in approximately 16% of non–small cell lung cancer (NSCLC),9,10 6% of small cell lung carcinomas,11 5% of hormone receptor (HR)-positive breast cancers,12 and 4% of triple-negative breast cancers.13 FGFR2 amplification was demonstrated in approximately 4% of gastric cancers14 and 4% of triple negative breast cancers.13 However, gastric and breast cancer cell lines with FGFR2 amplifications were particularly sensitive to selective FGFR inhibitors, suggesting that the FGFR2 amplification confers addiction to the FGFR pathway.15,16 FGFR3 amplification is relatively uncommon but was demonstrated in 3% of urothelial cancers.8

Activating mutations in FGFR3 are particularly prevalent in urothelial cancers, occurring in up to 80% of nonmuscle invasive urothelial cell carcinomas, 20% of high-grade invasive urothelial cancers, and 5% of cervical cancers.12 Activating mutations in FGFR2 occur in 12% to 14% of endometrial cancers and have been demonstrated in a small proportion of squamous NSCLCs, gastric cancers, and urothelial cancers.8,12 Activating mutations in FGFR1 and FGFR4 are relatively uncommon and have been observed in pilocytic astrocytoma (FGFR1) and rhabdomyosarcoma (FGFR4).12

FGFR3 translocations/fusions account for 15% to 20% of multiple myelomas and have been observed in glioblastoma and bladder cancer.12 FGFR2 translocations are found in approximately 14% of intrahepatic cholangiocarcinomas and occur occasionally in lung, thyroid, and prostate cancer.12,17,18 FGFR1 translocations are relatively uncommon but have been observed in glioblastoma, breast cancer, squamous cell lung carcinoma, and 8p11 myeloproliferative syndrome.12

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TitleExpiration DateCME Credits
Community Practice Connections™: 14th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 30, 20192.0
Oncology Consultations®: The Advancing Role of CAR T-Cell Therapies in Hematologic MalignanciesApr 30, 20191.5
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