Dual Antagonist of cIAP/XIAP ASTX660 Sensitizes HPV− and HPV+ Head and Neck Cancers to TNFα, TRAIL, and Radiation Therapy

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Abstract
Purpose: Human papilloma virus (HPV) negative head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-Associated Death Domain (FADD), with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV(-), but not HPV(+) tumors, to Tumor Necrosis Factor family death ligands (TNF, TRAIL) and radiation. Methods: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV(+) and (-) cell lines in combination with death ligands TNF and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion. Results: ASTX660 sensitized subsets of HPV(-) and (+) HNSCC cell lines to TNFα and TRAIL. These anti-tumor effects of ASTX660 are the result of both apoptosis and/or necroptosis among HPV(-) cells, and primarily by apoptosis (caspase 3 and caspase 8 cleavage) in HPV(+) cells. ASTX660 enhanced restoration of protein expression and inhibitory activity of pro-apoptotic tumor suppressor TP53 in HPV(+) HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both human HPV(-) and HPV(+) human tumor xenografts, an effect attenuated by anti-TNFα pretreatment blockade. Conclusions: IAP1/XIAP antagonist ASTX660 sensitizes HPV(+) HNSCC to TNFα via a mechanism involving restoration of TP53. The present findings serve to motivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV(+) and (-) HNSCC.
Funding Information
  • NIDCD (ZIA-DC-000016, 73, 74)
  • NIDCD (87)
  • NIDCD (90)
  • Doris Duke Charitable Foundation (#2014194)

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