期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 107, 期 11, 页码 -出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djv247
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资金
- National Institute of Health [UO1GM61393, K08GM089941, R21 CA139278]
- Circle of Service Foundation Early Career Investigator award
- University of Chicago CTSA core subsidy grant
- Conquer Cancer Foundation of ASCO Translational Research Professorship Award In Memory of Merrill J. Egorin, MD
- University of Chicago [P30 CA14599]
- Breast Cancer SPORE Career Development Award [CA125183]
- National Center for Advancing Translational Sciences of the National Institute of Health [UL1RR024999]
- Chicago Biomedical Consortium grant [PDR-020]
- Investigational Drug Branch of the US National Cancer Institute [U01 CA069852]
- [UM1 CA186705]
Background: Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated. Methods: We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation. We compared different approaches in terms of how accurately vorinostat response can be predicted on an independent out-of-batch set of samples and applied the polygenic marker prediction principles in a clinical trial. Results: Using machine learning, the small effects that aggregate, resulting in sensitivity or resistance, can be recovered from gene expression data in a large panel of cancer cell lines. This approach can predict vorinostat response accurately, whereas single gene or pathway markers cannot. Our analyses recapitulated and contextualized many previous findings and suggest an important role for processes such as chromatin remodeling, autophagy, and apoptosis. As a proof of concept, we also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. As a clinical validation, we demonstrated that a common dose-limiting toxicity of vorinostat, thrombocytopenia, can be predicted (r = 0.55, P = .004) several days before it is detected clinically. Conclusion: Our work suggests a paradigm shift from single-gene/pathway evaluation to simultaneously evaluating multiple independent high-throughput gene expression datasets, which can be easily extended to other investigational compounds where similar issues are hampering clinical adoption.
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