Polyclonal Secondary <i>FGFR2</i> Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma
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- Lipika Goyal
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Supriya K. Saha
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Leah Y. Liu
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Giulia Siravegna
- 2Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
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- Ignaty Leshchiner
- 5Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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- Leanne G. Ahronian
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Jochen K. Lennerz
- 6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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- Phuong Vu
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Vikram Deshpande
- 6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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- Avinash Kambadakone
- 7Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
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- Benedetta Mussolin
- 2Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
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- Stephanie Reyes
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Laura Henderson
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Jiaoyuan Elisabeth Sun
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Emily E. Van Seventer
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Joseph M. Gurski
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Sabrina Baltschukat
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Barbara Schacher-Engstler
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Louise Barys
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Christelle Stamm
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Pascal Furet
- 9Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland.
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- David P. Ryan
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- James R. Stone
- 6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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- A. John Iafrate
- 6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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- Gad Getz
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Diana Graus Porta
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Ralph Tiedt
- 8Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
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- Alberto Bardelli
- 2Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
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- Dejan Juric
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Ryan B. Corcoran
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Nabeel Bardeesy
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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- Andrew X. Zhu
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Description
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>See related commentary by Smyth et al., p. 248.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 235</jats:p>
Journal
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- Cancer Discovery
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Cancer Discovery 7 (3), 252-263, 2017-03-01
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1362262944554032128
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- ISSN
- 21598290
- 21598274
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- Data Source
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- Crossref