RRC ID 66894
Author Goyal L, Shi L, Liu LY, Fece de la Cruz F, Lennerz JK, Raghavan S, Leschiner I, Elagina L, Siravegna G, Ng RWS, Vu P, Patra KC, Saha SK, Uppot RN, Arellano R, Reyes S, Sagara T, Otsuki S, Nadres B, Shahzade HA, Dey-Guha I, Fetter IJ, Baiev I, Van Seventer EE, Murphy JE, Ferrone CR, Tanabe KK, Deshpande V, Harding JJ, Yaeger R, Kelley RK, Bardelli A, Iafrate AJ, Hahn WC, Benes CH, Ting DT, Hirai H, Getz G, Juric D, Zhu AX, Corcoran RB, Bardeesy N.
Title TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.
Journal Cancer Discov
Abstract ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.
Volume 9(8)
Pages 1064-1079
Published 2019-8-1
DOI 10.1158/2159-8290.CD-19-0182
PII 2159-8290.CD-19-0182
PMID 31109923
PMC PMC6677584
MeSH Adenosine Triphosphate / metabolism* Adult Aged Cell Line, Tumor Cholangiocarcinoma / diagnosis Cholangiocarcinoma / genetics* Cholangiocarcinoma / metabolism* Circulating Tumor DNA Drug Resistance, Neoplasm / genetics* Female Humans Male Middle Aged Mutation Oncogene Proteins, Fusion / antagonists & inhibitors Oncogene Proteins, Fusion / genetics Phenylurea Compounds / pharmacology Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Pyrimidines / pharmacology Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors* Receptor, Fibroblast Growth Factor, Type 2 / chemistry Receptor, Fibroblast Growth Factor, Type 2 / genetics* Receptor, Fibroblast Growth Factor, Type 2 / metabolism Signal Transduction / drug effects Structure-Activity Relationship Tomography, X-Ray Computed
IF 29.497
Human and Animal Cells HuCCT1(RCB1960) RBE(RCB1292) SSP-25(RCB1293) HuH-28(RCB1943)