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Ref Type Journal Article
PMID (31911531)
Authors Krook MA, Lenyo A, Wilberding M, Barker H, Dantuono M, Bailey KM, Chen HZ, Reeser JW, Wing MR, Miya J, Samorodnitsky E, Smith AM, Dao T, Martin DM, Ciombor KK, Hays J, Freud AG, Roychowdhury S
Title Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma.
Journal Molecular cancer therapeutics
Vol 19
Issue 3
Date 2020 Mar
URL
Abstract Text The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.

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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 E565A missense gain of function FGFR2 E565A lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E565A demonstrates resistance to FGFR inhibitors in the context of FGFR2-SHTN1 in culture (PMID: 31911531), and results in increased Fgfr2 autophosphorylation and substrate phosphorylation in in vitro kinase assays (PMID: 17803937, PMID: 28166054). Y
FGFR2 SHTN1 FGFR2 - SHTN1 fusion gain of function - predicted FGFR2-SHTN1 (also referred to as FGFR2-KIAA1598) results from the fusion of FGFR2 and SHTN1, which has been demonstrated to result in increased phosphorylation of recombinant protein S6, Akt, and mTOR in cultured cells (PMID: 31911531), and therefore, is predicted to lead to a gain of protein function. FGFR2-SHTN1 has been identified in cholangiocarinoma (PMID: 25536104, PMID: 31911531) and non-small cell lung cancer (PMID: 30267839).
FGFR2 L617M missense unknown FGFR2 L617M lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L617M has been demonstrated to confer resistance to FGFR inhibitors as a secondary resistance mutation in the context of FGFR2 fusions (PMID: 31911531), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jan 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor sensitive Erdafitinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A to treatment with Balversa (erdafitinib), demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing FGFR2-SHTN1 demonstrated resistance to treatment with Dovitinib (TKI258) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Infigratinib (BGJ398) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Dovitinib (TKI258) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2-SHTN1 were sensitive to treatment with Balversa (erdafitinib), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor sensitive Ponatinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of Iclusig (ponatinib) and Sapanisertib (MLN0128) resulted in synergistic effects in transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Balversa (erdafitinib) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M cholangiocarcinoma resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with AZD4547 in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with AZD4547 in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A FGFR2 L617M cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a Phase II trial, a patient with cholangiocarcinoma harboring FGFR2-SHTN1 initially responded to treatment with Infigratinib (BGJ398), but progressed after eight months and via repeat tissue biopsy was found to have acquired FGFR2 E565A, and via circulating tumor DNA testing, FGFR2 L617M (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Dovitinib (TKI258) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 Advanced Solid Tumor sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2-SHTN1 were sensitive to treatment with AZD4547, demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with Infigratinib (BGJ398) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with Infigratinib (BGJ398) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor sensitive Erdafitinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M to treatment with Balversa (erdafitinib), demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2-SHTN1 were sensitive to treatment with Iclusig (ponatinib), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing FGFR2-SHTN1 were sensitive to treatment with Balversa (erdafitinib), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Balversa (erdafitinib) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A were sensitive to treatment with Iclusig (ponatinib) in culture, demonstrating reduced cell viability (PMID: 31911531). 31911531
FGFR2 - SHTN1 Advanced Solid Tumor sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2-SHTN1 were sensitive to treatment with Futibatinib (TAS-120), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Infigratinib (BGJ398) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 Advanced Solid Tumor resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2-SHTN1 demonstrated resistance to treatment with Dovitinib (TKI258) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor sensitive AZD4547 + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M to treatment with AZD4547, demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A FGFR2 L617M Advanced Solid Tumor sensitive Infigratinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A to treatment with Infigratinib (BGJ398), demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing FGFR2-SHTN1 were sensitive to treatment with AZD4547, demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M were sensitive to treatment with Iclusig (ponatinib) in culture, demonstrating reduced cell viability (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M cholangiocarcinoma resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with Futibatinib (TAS-120) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with AZD4547 in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing FGFR2-SHTN1 were sensitive to treatment with Iclusig (ponatinib), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma predicted - sensitive Infigratinib Case Reports/Case Series Actionable In a Phase II trial, a patient with cholangiocarcinoma harboring FGFR2-SHTN1 experienced a partial response according to RECIST criteria after four months of treatment with Infigratinib (BGJ398) (PMID: 31911531). 31911531
FGFR2 - SHTN1 cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing FGFR2-SHTN1 were sensitive to treatment with Futibatinib (TAS-120), demonstrating decreased cell viability in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M cholangiocarcinoma resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with Balversa (erdafitinib) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Futibatinib (TAS-120) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A cholangiocarcinoma resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with Futibatinib (TAS-120) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor sensitive AZD4547 + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A to treatment with AZD4547, demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M demonstrated resistance to treatment with Balversa (erdafitinib) in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A were sensitive to treatment with Iclusig (ponatinib) in culture, demonstrating reduced cell viability (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M cholangiocarcinoma sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, cholangiocarcinoma cells expressing both FGFR2-SHTN1 and FGFR2 E565A were sensitive to treatment with Iclusig (ponatinib) in culture, demonstrating reduced cell viability (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 L617M Advanced Solid Tumor sensitive Infigratinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sapanisertib (MLN0128) therapy restored the sensitivity of transformed cells expressing both FGFR2-SHTN1 and FGFR2 L617M to treatment with Infigratinib (BGJ398), demonstrating synergistic effects (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A demonstrated resistance to treatment with AZD4547 in culture (PMID: 31911531). 31911531
FGFR2 - SHTN1 FGFR2 E565A Advanced Solid Tumor sensitive Ponatinib + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of Iclusig (ponatinib) and Sapanisertib (MLN0128) resulted in synergistic effects in transformed cells expressing both FGFR2-SHTN1 and FGFR2 E565A in culture (PMID: 31911531). 31911531