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Ref Type Journal Article
PMID (32370101)
Authors Lima NC, Atkinson E, Bunney TD, Katan M, Huang PH
Title Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.
URL
Abstract Text Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR3 K652E missense gain of function - predicted FGFR3 K652E (corresponds to K650E in the canonical isoform) lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). K652E results in constitutive phosphorylation of Src, Akt and Erk phosphorylation similar to wild-type Fgfr3, and anchorage-independent growth in cultured cells (PMID: 32370101), and has been demonstrated to induce transformation of mouse fibroblasts, but has a lesser degree of signaling and phenotypic effect in immortalized normal human urothelial cells (PMID: 19749790), and therefore, is predicted to lead to a gain of Fgfr3 protein function. Y
FGFR3 N542K missense gain of function FGFR3 N542K (corresponds to N540K in the canonical isoform) lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). N542K confers a gain of function to Fgfr3 as demonstrated by constitutive Src phosphorylation and anchorage-independent growth in cultured cells (PMID: 32370101).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C Advanced Solid Tumor resistant Dasatinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing FGFR3 S249C was resistant to Sprycel (dasatinib) treatment in culture (PMID: 32370101). 32370101
FGFR3 S249C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cell line expressing FGFR3 S249C in culture (PMID: 32370101). 32370101
FGFR3 N542K Advanced Solid Tumor sensitive Dasatinib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Sprycel (dasatinib) treatment inhibited viability of a cell line expressing FGFR3 N542K in culture (PMID: 32370101). 32370101
FGFR3 S249C Advanced Solid Tumor sensitive Dasatinib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Sprycel (dasatinib) treatment inhibited viability of a cell line expressing FGFR3 S249C in culture (PMID: 32370101). 32370101
FGFR3 K652E Advanced Solid Tumor sensitive Dasatinib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Truseltiq (infigratinib) and Sprycel (dasatinib) treatment inhibited viability of a cell line expressing FGFR3 K652E in culture (PMID: 32370101). 32370101
FGFR3 R248C transitional cell carcinoma sensitive Dasatinib + PD173074 Preclinical - Cell culture Actionable In a preclinical study, the addition of Sprycel (dasatinib) to treatment with PD173074 enhanced inhibition of colony formation of a urothelial cancer cell line harboring FGFR3 R248C in culture (PMID: 32370101). 32370101
FGFR3 N542K Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cell line expressing FGFR3 N542K in culture (PMID: 32370101). 32370101
FGFR3 K652E Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cell line expressing FGFR3 K652E in culture (PMID: 32370101). 32370101
FGFR3 R248C transitional cell carcinoma sensitive Dasatinib + Infigratinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sprycel (dasatinib) to treatment with Truseltiq (infigratinib) enhanced inhibition of colony formation and synergistically decreased viability in a urothelial cancer cell line harboring FGFR3 R248C in culture (PMID: 32370101). 32370101