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2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology. | LitMetric

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology.

J Oncol

New Hope Cancer Center, Beijing United Hospital, 9-11 Jiangtai West Rd, Chaoyang, Beijing 100015, China.

Published: April 2021

AI Article Synopsis

Article Abstract

More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition. The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. Exclusive use of small-molecule pan-FGFR inhibitors may thus cause nonselective blockade of FGFR2 isoforms with opposing actions, undermining the rationale of FGFR2 drug targeting. This splice-dependent ability of FGFR2 to switch between tumor-suppressing and -driving functions highlights an unmet oncologic need for isoform-specific drug targeting, e.g., by antibody inhibition of ligand-FGFR2c binding, as well as for more nuanced molecular pathology prediction of FGFR2 actions in different stromal-tumor contexts.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110382PMC
http://dx.doi.org/10.1155/2021/9955456DOI Listing

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