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

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.

Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma

“…This indicates that better predictive biomarkers are still needed for FGFR precision targeted therapy. Indeed, FGFR2 isoform status may play a role in predicting response to FGFR inhibitors in several solid cancer types [ 42 ].…”

In vitro study of the antimitotic power and in vivo acute toxicity of aqueous and organic extracts of the aerial part of Haloxylon scoparium Pomel. and evaluation of the correlation between the chemical profile and their biological activities

“…In addition, some new anticancer molecules can cause toxicities, particularly cutaneous toxicities. For example, they can concern until 80% of the patients treated by the inhibitors of the epidermal growth factor EGF-R (4)(5)(6)(7)(8)(9). Faced with this situation, some patients have recourse to phytotherapy either for the treatment of cancer or to attenuate its undesirable effects; the multiplication of recourse to complementary and alternative medicine (CAM), particularly developed in the field of cancer with the aim of relieving physical or psychological suffering, improving the quality of life, fighting against cancer or its recurrence (10)(11)(12).…”

Fine‐Tuning the Relevance of Molecular Targets to Pediatric Cancer: Addressing Additional Layers of Complexity

“…In addition, mutations may have different functional impact according with the splice isoform 5 . Therapeutic agents that simultaneously inhibit splice isoforms with opposing or unique roles could have unintended effects 7 …”

“…5 Therapeutic agents that simultaneously inhibit splice isoforms with opposing or unique roles could have unintended effects. 7 Table 1 provides five illustrative examples of genes included in the Relevant…”