TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma
| Autor: | Islam Baiev, Raul N. Uppot, Leah Y. Liu, Giulia Siravegna, Isobel J Fetter, Stephanie Reyes, Dejan Juric, Cristina R. Ferrone, Emily E. Van Seventer, David T. Ting, Sachie Otsuki, Ipsita Dey-Guha, Jochen K. Lennerz, William C. Hahn, Lei Shi, Krushna C. Patra, Ignaty Leschiner, Gad Getz, Heather A. Shahzade, Cyril H. Benes, Phuong Vu, Robin Kate Kelley, Liudmila Elagina, Vikram Deshpande, Hiroshi Hirai, James J. Harding, Alberto Bardelli, Ferran Fece de la Cruz, Andrew X. Zhu, A. John Iafrate, Raymond W.S. Ng, Nabeel Bardeesy, Takeshi Sagara, Kenneth K. Tanabe, Rona Yaeger, Supriya K. Saha, Srivatsan Raghavan, Brandon Nadres, Janet E. Murphy, Ryan B. Corcoran, Ronald S. Arellano, Lipika Goyal |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Fibroblast Growth Factor Oncogene Proteins Fusion Cell Drug Resistance Drug resistance medicine.disease_cause Circulating Tumor DNA Cholangiocarcinoma 0302 clinical medicine Adenosine Triphosphate Erdafitinib Medicine Tomography Cancer Oncogene Proteins Mutation Tumor Kinase Middle Aged X-Ray Computed medicine.anatomical_structure Oncology Fibroblast growth factor receptor 030220 oncology & carcinogenesis embryonic structures Female Type 2 Receptor Signal Transduction musculoskeletal diseases Adult animal structures FGFR Inhibition Oncology and Carcinogenesis Article Cell Line 03 medical and health sciences Structure-Activity Relationship Cell Line Tumor Genetics Humans Receptor Fibroblast Growth Factor Type 2 Fusion Protein Kinase Inhibitors Aged business.industry Phenylurea Compounds 030104 developmental biology Pyrimidines Tumor progression Drug Resistance Neoplasm Cancer research Neoplasm business Tomography X-Ray Computed |
| Zdroj: | Cancer Discov Cancer discovery, vol 9, iss 8 |
| ISSN: | 2159-8290 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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