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

Autor:	Goyal L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Saha SK; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Liu LY; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Siravegna G; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Torino, Italy.; Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology (IFOM), Milano, Italy., Leshchiner I; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts., Ahronian LG; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Lennerz JK; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts., Vu P; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Deshpande V; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts., Kambadakone A; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts., Mussolin B; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy., Reyes S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Henderson L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Sun JE; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Van Seventer EE; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Gurski JM Jr; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Baltschukat S; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Schacher-Engstler B; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Barys L; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Stamm C; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Furet P; Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland., Ryan DP; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Stone JR; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts., Iafrate AJ; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts., Getz G; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts., Porta DG; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Tiedt R; Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland., Bardelli A; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Torino, Italy., Juric D; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Corcoran RB; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org., Bardeesy N; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org., Zhu AX; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2017 Mar; Vol. 7 (3), pp. 252-263. Date of Electronic Publication: 2016 Dec 29.
DOI:	10.1158/2159-8290.CD-16-1000
Abstrakt:	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 intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies. Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR. See related commentary by Smyth et al., p. 248 This article is highlighted in the In This Issue feature, p. 235 . (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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