HORMAD1 Is a Negative Prognostic Indicator in Lung Adenocarcinoma and Specifies Resistance to Oxidative and Genotoxic Stress
Abstract
Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non–small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth in vivo. These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2018
- Source ID
- 10.1158/0008-5472.can-18-1377
Entities
People
- Angelique W. Whitehurst
- Anthony J. Davis
- Brandt A. Nichols
- Bruce A. Posner
- Elizabeth A. Mcmillan
- Ignacio I. Wistuba
- Jaime Rodriguez-canales
- Janapriya Saha
- Jingsheng Yan
- John B. MacMillan
- John Minna
- Kathleen Mcglynn
- Min S. Kim
- Nathaniel W. Oswald
- Pamela A. Villalobos
- Prema L. Mallipeddi
- Sydnie A. Laduke
Organizations
- American Association for Cancer Research
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- National Institute of General Medical Sciences
- The University of Texas MD Anderson Cancer Center
- Tobacco-Related Disease Research Program
- United States Department of Defense
- University of California, Santa Cruz
- University of Texas Southwestern Medical Center