TABLE 1.
Overview of recent key preclinical and clinical findings on FGFR3 mutations in BLCA.
| Recent findings on FGFR3 mutations in BLCA | Preclinical | Clinical |
|---|---|---|
| Related to TME and CPIs | ||
| Immune‐inert phenotype in FGFR3 mutated tumors in mice | ✓ | |
| Downregulation of PD‐L1 in FGFR3 active status | ✓ | |
| Impact on anti‐tumor activity of CD8+ T‐cells | ✓ | |
| Improved antitumor effect upon combining FGFR3 and PD‐1 targeting | ✓ | |
| Reduced T‐cell infiltration and inert microenvironment associated with FGFR3 mutations in BLCA patients | ✓ | |
| FGFR3 mutation impacts response to CPIs by both T‐cell infiltration and stroma‐associated EMT markers | ✓ | |
| Cold tumors not always in inverse relationship with responsiveness to CPIs in FGFR3‐altered BLCA patients | ✓ | |
| Related to FGFR3 inhibition and resistance | ||
| EGFR and PI3K identified as co‐targets | ✓ | |
| Sensitivity in FGFR3 resistant cell lines when co‐targeting EGFR | ✓ | |
| bypassing mechanisms through effectors of AKT pathway | ✓ | |
| Heterogenous phenotypic switches in FGFR3‐resistant subclones derived from the same cell | ✓ | |
| Upregulation of various genes including IGF1R, EGFR, ERBB2, ERBB3, and MET | ✓ | |
| Quisinostat synergizes with Erdafitinib by suppressing FGFR3 protein translation | ✓ | |
| Resistance to Erdafitinib in FGFR3 mutant cells induced by P4HA2 and HIF‐1α | ✓ | |
| NRG1‐HER3 axis mediates resistance to Erdafitinib and sensitizes to HER3‐targeting in FGFR3 mut BLCA mouse xenografts | ✓ | |
| Secondary mutations at gatekeeper residue sites | ✓ | |
| HRAS mutation was found in some FGFR3‐resistant sub‐clones | ✓ | |
| Resistance hotspot mutations on residues V555 and N540 | ✓ | |
| Genetic alterations within AKT pathway effectors | ✓ | |
| Poorer outcome upon baseline co‐occurrence of FGFR3 and TP53 mutations | ✓ |
Different phenomena discovered preclinically or clinically concerning the impact of FGFR3 alterations on TME, response to CPIs, and response and resistance to FGFR inhibition are summarized.
Abbreviations: BLCA, Bladder Cancer; CPIs, Checkpoint Inhibitors; FGFR3, Fibroblast Growth Factor Receptor 3; FGFR, Fibroblast Growth Factor Receptor; TME, Tumor Microenvironment.