Abstract
Purpose: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers. Experimental Design:Wetested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patientderived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression. Results: Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that themechanismof sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition-induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells' sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reducedAurora kinase inhibition-induced apoptosis,whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells. Conclusions: Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.
Original language | English |
---|---|
Pages (from-to) | 4479-4493 |
Number of pages | 15 |
Journal | Clinical Cancer Research |
Volume | 28 |
Issue number | 20 |
DOIs | |
State | Published - 14 Oct 2022 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 American Association for Cancer Research.
Funding
C. Stephan reports grants from Cancer Prevention and Research Institute of Texas during the conduct of the study. C.R. Pickering reports grants from NIH outside the submitted work. F.M. Johnson reports grants from Takeda, Viractra, and Trovagene outside the submitted work. No disclosures were reported by the other authors. This work was supported by the NIH (R01CA248205; to F.M. Johnson); philanthropic contributions from Mr. and Mrs. Charles W. Stiefel to The University of Texas MD Anderson Cancer Center-Oropharynx Cancer Program (to F.M. Johnson, C.R. Pickering); and the Cancer Prevention and Research Institute of Texas (RP150578; to C. Stephan). This work used the services of MD Anderson’s Flow Cytometry and Cellular Imaging Facility and Bioinformatics Shared Resource, which are supported by the NIH through MD Anderson’s Cancer Center Support Grant (P30CA016672). We would like to thank all members of the Flow Cytometry & Cellular Imaging facility, which is supported in part by the NIH through MD Anderson’s Cancer Center Support Grant CA016672. We would also like to thank Laura L. Russell, scientific editor of MD Anderson, Research Medical Library, for editing this article.
Funders | Funder number |
---|---|
University of Texas MD Anderson Cancer Center-Oropharynx Cancer Program | |
National Institutes of Health | |
National Cancer Institute | R01CA248205 |
Cancer Prevention and Research Institute of Texas | P30CA016672, CA016672, RP150578 |