Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer (Gut, Jan 2013)

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely-used chemotherapy agent used to treat several gastrointestinal cancers, including gastric cancer (GC). However, there are currently no established approaches for accurately identifying which GC patients are most likely to respond to cisplatin prior to treatment. In this study, we combined DNA methylation (epigenetic) and gene expression data in GC cell lines and primary tumors to identify the BMP4 gene as a novel modulator of cisplatin resistance. Using a variety of experimental assays, we found BMP4 drives multiple aspects of cancer progression, and patients with tumors expressing high level of BMP4 exhibited poor prognosis. Using a genetic strategy, we demonstrated that inhibiting BMP4 sensitizes GC cells to cisplatin, and that BMP4-high gastric cancers did not exhibit cross-resistance to oxaliplatin, a related chemotherapy drug. These results suggest that targeting BMP4 may represent a promising therapeutic strategy for sensitizing GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin-alternative, may also represent a therapeutic option for BMP4-positive GCs.



Tatiana Ivanova1, Hermioni Zouridis1, Lai Ling Cheng1,2, Iain Beehuat Tan3, Yonghui Wu4, Veena Gopalakrishnan1, Chia Huey Ooi1, Julian Lee4, Luo Qin1, Jeanie Wu4, Minghui Lee4, Sun Young Rha5, Dan Huang6, Natalia Liem7, Khay Guan Yeoh8, Wei Peng Yong9, Teh Bin Tean10, Patrick Tan1,4,7,11,*

1Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857

2Singapore-MIT Alliance/7Cancer Science Institute of Singapore, National University of Singapore, 5 Lower Kent Ridge Road, Singapore, 119074

3Division of Medical Oncology

4Cellular and Molecular Research/9NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore, 169610

5Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, Seoul, Korea 120-752

6Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA

8Department of Medicine/9National Cancer Institute, National University Hospital Singapore

10Genome Institute of Singapore, 60 Biopolis Street Genome #02-01, Singapore, 138672

Link to PubMed