Journal
NATURE METABOLISM
Volume 1, Issue 4, Pages 431-444Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-019-0045-8
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Funding
- Cancer Prevention & Research Institute of Texas [RR150085, RP140462, RP150094, RP180259, R1218]
- National Institutes of Health [CA168394, CA098258, CA143883, CA175486, CA209851, R00DK094981, 1R01CA218025, 1R01CA231011, R00CA166527, 1R01CA218036, R01 HL137990, 1R01HL136969]
- Department of Defense [BC180196, BC151465]
- American Association for Cancer Research-Bayer Innovation and Discovery Grant [18-80-44]
- Andrew Sabin Family Foundation
- MD Anderson Physician Scientist Award
- Khalifa Physician Scientist Award
- Andrew Sabin Family Foundation Fellows Award
- MD Anderson Faculty Scholar Award
- Doris Duke Charitable Foundation Career Development Award [2018097]
- National Natural Science Foundation of China [81822034, 81773119]
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Tumour hypoxia is a major contributor to resistance to anticancer therapies. Given that the results of hypoxia-targeted therapy trials have been disappointing, a more personalized approach may be needed. Here, we characterize multi-omic molecular features associated with tumour hypoxia and identify molecular alterations that correlate with both drug-resistant and drugsensitive responses to anticancer drugs. Based on a well-established hypoxia gene expression signature, we classify about 10,000 tumour samples into hypoxia score-high and score-low groups across different cancer types from The Cancer Genome Atlas (TCGA) and demonstrate their prognostic associations. Then, we identify various types of molecular features associated with hypoxia status that correlate with drug resistance but, in some cases, also with drug sensitivity, contrasting the conventional view that hypoxia confers drug resistance. We further show that 110 out of 121 (90.9%) clinically actionable genes can be affected by hypoxia status and experimentally validate the predicted effects of hypoxia on the response to several drugs in cultured cells. Our study provides a comprehensive molecular-level understanding of tumour hypoxia and may have practical implications for clinical cancer therapy.
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