Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of molecular sciences	21	9	2020 May 01		Int J Mol Sci

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 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 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 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 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 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
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 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