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Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma

2016; American Association for Cancer Research; Volume: 7; Issue: 3 Linguagem: Inglês

10.1158/2159-8290.cd-16-1000

2159-8290

Lipika Goyal, Supriya K. Saha, Leah Y. Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G. Ahronian, Jochen K. Lennerz, Phuong Vu, Vikram Deshpande, Avinash Kambadakone, Benedetta Mussolin, Stephanie Reyes, Laura E. Henderson, Jiaoyuan Elisabeth Sun, Emily E. Van Seventer, Joseph M. Gurski, Sabrina Baltschukat, Barbara Schacher-Engstler, Louise Barys, Christelle Stamm, Pascal Furet, David P. Ryan, James R. Stone, A. John Iafrate, Gad Getz, Diana Graus Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B. Corcoran, Nabeel Bardeesy, Andrew X. Zhu,

Cancer Genomics and Diagnostics

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the