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Ref Type Journal Article
PMID (37377403)
Authors Facchinetti F, Hollebecque A, Braye F, Vasseur D, Pradat Y, Bahleda R, Pobel C, Bigot L, Deas O, Florez Arango JD, Guaitoli G, Mizuta H, Combarel D, Tselikas L, Michiels S, Nikolaev SI, Scoazec JY, Ponce-Aix S, Besse B, Olaussen KA, Loriot Y, Friboulet L
Title Resistance to selective FGFR inhibitors in FGFR-driven urothelial cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Jun 28 Cancer Discov
URL
Abstract Text Several FGFR inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 FGFR-driven urothelial cancer patients treated with selective FGFR inhibitors and analyzed post-progression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 5 TSC1/2, n = 5 PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergic with pictilisib in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.

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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
FGFR2 L551F missense unknown FGFR2 L551F lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L551F has been associated with resistance to some FGFR inhibitors in cell culture (PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Feb 2024). Y
FGFR3 E587Q missense unknown FGFR3 E587Q lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). E587Q has been identified in the scientific literature (PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Jan 2024).
FGFR3 V553L missense unknown FGFR3 V553L lies within the protein kinase domain (UniProt.org). V553L has been identified in the scientific literature (PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Dec 2023).
FGFR3 V553M missense unknown FGFR3 V553M lies within the protein kinase domain (UniProt.org). V553M has been associated with FGFR inhibitor resistance (PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Feb 2024). Y
FGFR3 V555L missense unknown FGFR3 V555L lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V555L has been demonstrated to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880, PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Dec 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C PIK3CA E545K bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, PIK3CA E545K was identified in the post-progression biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C who progressed on treatment with Balversa (erdafitinib) (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545K transitional cell carcinoma sensitive Erdafitinib + Pictilisib Preclinical - Pdx & cell culture Actionable In a preclinical study, combination treatment with Balversa (erdafitinib) and Pictilisib (GDC-0941) resulted in synergistic inhibition of tumor growth in a patient-derived xenograft (PDX) model of urothelial cancer harboring FGFR3 S249C and PIK3CA E545K (PMID: 37377403). 37377403
FGFR3 Y373C FGFR3 N540K FGFR3 V555L FGFR3 L608V bladder urothelial carcinoma predicted - resistant Futibatinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 N540K, FGFR3 V555L, and FGFR3 L608V were identified in the post-progression circulating tumor DNA of a patient with bladder urothelial carcinoma harboring FGFR3 Y373C who previously responded to Lytgobi (futibatinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545K bladder urothelial carcinoma predicted - resistant Futibatinib Case Reports/Case Series Actionable In a clinical case study, a patient with bladder urothelial cancer harboring FGFR3 S249C and an acquired PIK3CA E545K experienced primary resistance to treatment with Lytgobi (futibatinib) (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 amp PTEN C136fs transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, PTEN C136fs and FGFR3 amplification (6 copies) were identified in the tissue biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C who progressed on Balversa (erdafitinib) after 1.4 months of treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V555L transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V555L was identified in the post-progression circulating tumor DNA of a patient with urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C transitional cell carcinoma sensitive Erdafitinib + Gefitinib Preclinical - Pdx & cell culture Actionable In a preclinical study, combination treatment with Balversa (erdafitinib) and Iressa (gefitinib) inhibited cell growth of patient-derived urothelial cancer cells harboring FGFR3 S249C and PIK3CA E545A in culture, and led to synergistic inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 37377403). 37377403
FGFR3 S249C transitional cell carcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, Pemazyre (pemigatinib) treatment resulted in a partial response with a progression-free survival of 8.3 months in a patient with urothelial cancer harboring FGFR3 S249C (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 N540K PIK3CA E545K transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 N540K was identified in the post-progression biopsy of a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and PIK3CA E545K who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V553L transitional cell carcinoma not predictive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553L was identified in the post-progression biopsy of a patient with upper tract urothelial carcinoma harboring FGFR3 S249C who previously responded to Pemazyre (pemigatinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C PIK3CA E545A transitional cell carcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 5.8 months in a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and PIK3CA E545A (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 V553M bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553M was identified in the post-progression circulating tumor DNA of a patient with bladder urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 Y373C bladder urothelial carcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, Pemazyre (pemigatinib) treatment resulted in a partial response with a progression-free survival of 8.4 months in a patient with bladder urothelial cancer harboring FGFR3 Y373C (PMID: 37377403). 37377403