Dual antagonist of cIAP/XIAP ASTX660 sensitizes HPV- and HPV+ head and neck cancers to TNFα, TRAIL, and radiation therapy

Roy Xiao, Yi An, Wenda Ye, Adeeb Derakhshan, Hui Cheng, Xinping Yang, Clint Allen, Zhong Chen, Nicole C. Schmitt, Carter Van Waes

Research output: Contribution to journalArticle

Abstract

Purpose: Human papillomavirus-negative (HPV-) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, 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 TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV- cell lines in combination with death ligands TNFα 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 HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor 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 proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both 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. These findings serve tomotivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV- HNSCC.

Original languageEnglish (US)
Pages (from-to)6463-6474
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2019

Fingerprint

Head and Neck Neoplasms
Radiotherapy
Inhibitor of Apoptosis Proteins
Ligands
Apoptosis
Heterografts
Radiation
Cell Line
Neoplasms
Caspase 8
Baculoviridae
Caspase 3
Research Design
Carcinoma, squamous cell of head and neck
Clinical Trials
Antibodies
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual antagonist of cIAP/XIAP ASTX660 sensitizes HPV- and HPV+ head and neck cancers to TNFα, TRAIL, and radiation therapy. / Xiao, Roy; An, Yi; Ye, Wenda; Derakhshan, Adeeb; Cheng, Hui; Yang, Xinping; Allen, Clint; Chen, Zhong; Schmitt, Nicole C.; Van Waes, Carter.

In: Clinical Cancer Research, Vol. 25, No. 21, 01.11.2019, p. 6463-6474.

Research output: Contribution to journalArticle

Xiao, Roy ; An, Yi ; Ye, Wenda ; Derakhshan, Adeeb ; Cheng, Hui ; Yang, Xinping ; Allen, Clint ; Chen, Zhong ; Schmitt, Nicole C. ; Van Waes, Carter. / Dual antagonist of cIAP/XIAP ASTX660 sensitizes HPV- and HPV+ head and neck cancers to TNFα, TRAIL, and radiation therapy. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 21. pp. 6463-6474.
@article{541435eb9cbb4042abf730596e524ab5,
title = "Dual antagonist of cIAP/XIAP ASTX660 sensitizes HPV- and HPV+ head and neck cancers to TNFα, TRAIL, and radiation therapy",
abstract = "Purpose: Human papillomavirus-negative (HPV-) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, 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 TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV- cell lines in combination with death ligands TNFα 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 HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor 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 proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both 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. These findings serve tomotivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV- HNSCC.",
author = "Roy Xiao and Yi An and Wenda Ye and Adeeb Derakhshan and Hui Cheng and Xinping Yang and Clint Allen and Zhong Chen and Schmitt, {Nicole C.} and {Van Waes}, Carter",
year = "2019",
month = "11",
day = "1",
doi = "10.1158/1078-0432.CCR-18-3802",
language = "English (US)",
volume = "25",
pages = "6463--6474",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

TY - JOUR

T1 - Dual antagonist of cIAP/XIAP ASTX660 sensitizes HPV- and HPV+ head and neck cancers to TNFα, TRAIL, and radiation therapy

AU - Xiao, Roy

AU - An, Yi

AU - Ye, Wenda

AU - Derakhshan, Adeeb

AU - Cheng, Hui

AU - Yang, Xinping

AU - Allen, Clint

AU - Chen, Zhong

AU - Schmitt, Nicole C.

AU - Van Waes, Carter

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Purpose: Human papillomavirus-negative (HPV-) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, 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 TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV- cell lines in combination with death ligands TNFα 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 HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor 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 proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both 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. These findings serve tomotivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV- HNSCC.

AB - Purpose: Human papillomavirus-negative (HPV-) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, 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 TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV- cell lines in combination with death ligands TNFα 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 HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor 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 proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both 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. These findings serve tomotivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV- HNSCC.

UR - http://www.scopus.com/inward/record.url?scp=85074377296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074377296&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-3802

DO - 10.1158/1078-0432.CCR-18-3802

M3 - Article

C2 - 31266830

AN - SCOPUS:85074377296

VL - 25

SP - 6463

EP - 6474

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -