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Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients

Goyal, Lipika and Supriya, Saha K and Liu, Lea Y and Siravegna, Giulia and Leshchiner, Ignaty and Ahronian, Leanne G and Lennerz, Jochen K and Vu, Phuong and Deshpande, Vikram and Kambadakone, Avinash and Mussolin, Benedetta and Reyes, Stephanie and Henderson, Laura and Sun, Jiaoyuan Elisabeth and Van Seventer, Emily E and Gurski, Joseph M Jr and Baltschukat, Sabrina and Schacher Engstler, Barbara and Barys, Louise and Furet, Pascal and Ryan, David P and Stone, James R and Iafrate, John A and Getz, Gad and Graus Porta, Diana and Tiedt, Ralph and Bardelli, Alberto and Juric, Dejan and Corcoran, Ryan B and Bardeesy, Nabeel and Zhu, Andrew X (2017) Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients. Cancer discovery. ISSN 2159-8290; 2159-8274

Abstract

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 FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance that was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide development of future therapeutic strategies.

Item Type: Article
Date Deposited: 15 Mar 2017 00:45
Last Modified: 15 Mar 2017 00:45
URI: https://oak.novartis.com/id/eprint/30875

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