TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma

Lipika Goyal, Lei Shi, Leah Y Liu, Ferran Fece de la Cruz, Jochen K Lennerz, Srivatsan Raghavan, Ignaty Leschiner, Liudmila Elagina, Giulia Siravegna, Raymond W S Ng, Phuong Vu, Krushna C Patra, Supriya K Saha, Raul N Uppot, Ron Arellano, Stephanie Reyes, Takeshi Sagara, Sachie Otsuki, Brandon Nadres, Heather A ShahzadeIpsita Dey-Guha, Isobel J Fetter, Islam Baiev, Emily E Van Seventer, Janet E Murphy, Cristina R Ferrone, Kenneth K Tanabe, Vikram Deshpande, James J Harding, Rona Yaeger, Robin K Kelley, Alberto Bardelli, A John Iafrate, William C Hahn, Cyril H Benes, David T Ting, Hiroshi Hirai, Gad Getz, Dejan Juric, Andrew X Zhu, Ryan B Corcoran, Nabeel Bardeesy

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1064-1079
Number of pages16
JournalCancer Discovery
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 2019

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Goyal, L., Shi, L., Liu, L. Y., Fece de la Cruz, F., Lennerz, J. K., Raghavan, S., Leschiner, I., Elagina, L., Siravegna, G., Ng, R. W. S., Vu, P., Patra, K. C., Saha, S. K., Uppot, R. N., Arellano, R., Reyes, S., Sagara, T., Otsuki, S., Nadres, B., ... Bardeesy, N. (2019). TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma. Cancer Discovery, 9(8), 1064-1079. https://doi.org/10.1158/2159-8290.CD-19-0182