TY - JOUR
T1 - HORMAD1 is a negative prognostic indicator in lung adenocarcinoma and specifies resistance to oxidative and genotoxic stress
AU - Nichols, Brandt A.
AU - Oswald, Nathaniel W.
AU - McMillan, Elizabeth A.
AU - McGlynn, Kathleen
AU - Yan, Jingsheng
AU - Kim, Min S.
AU - Saha, Janapriya
AU - Mallipeddi, Prema L.
AU - LaDuke, Sydnie A.
AU - Villalobos, Pamela A.
AU - Rodriguez-Canales, Jaime
AU - Wistuba, Ignacio I.
AU - Posner, Bruce A
AU - Davis, Anthony J
AU - Minna, John D
AU - MacMillan, John B
AU - Whitehurst, Angelique W
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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 g-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. Significance: This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC.
AB - 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 g-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. Significance: This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC.
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U2 - 10.1158/0008-5472.CAN-18-1377
DO - 10.1158/0008-5472.CAN-18-1377
M3 - Article
C2 - 30185546
AN - SCOPUS:85053735452
SN - 0008-5472
VL - 78
SP - 6196
EP - 6208
JO - Cancer research
JF - Cancer research
IS - 21
ER -