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Cancer Discov. 2016 Jul;6(7):727-39. doi: 10.1158/2159-8290.CD-15-1442. Epub 2016 May 26.

Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
3
Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts.
4
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California.
5
Wellcome Trust Sanger Institute, Hinxton, UK.
6
Department of Transplantation, Lahey Hospital and Medical Center, Burlington, Massachusetts.
7
Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts.
8
University of Rochester School of Medicine, Rochester, New York.
9
Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
10
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan.
11
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California.
12
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nelbardeesy@partners.org cbenes@mgh.harvard.edu.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness.

SIGNIFICANCE:

IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727-39. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

PMID:
27231123
PMCID:
PMC5458737
DOI:
10.1158/2159-8290.CD-15-1442
[Indexed for MEDLINE]
Free PMC Article

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