Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division

Replogle, J. M., Zhou, W., Amaro, A. E., McFarland, J. M., Villalobos-Ortiz, M., Ryan, J., Letai, A., Yilmaz, O., Sheltzer, J., Lippard, S. J., Ben-David, U., Amon, A. (December 2020) Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proc Natl Acad Sci U S A, 117 (48). pp. 30566-30576. ISSN 0027-8424 (Print)0027-8424

DOI: 10.1073/pnas.2009506117


Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition-G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.

Item Type: Paper
Additional Information: 1091-6490 Replogle, John Michael Zhou, Wen Orcid: 0000-0001-8455-6011 Amaro, Adrianna E McFarland, James M Villalobos-Ortiz, Mariana Ryan, Jeremy Orcid: 0000-0002-3327-1283 Letai, Anthony Yilmaz, Omer Sheltzer, Jason Lippard, Stephen J Ben-David, Uri Amon, Angelika HHMI/Howard Hughes Medical Institute/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30566-30576. doi: 10.1073/pnas.2009506117. Epub 2020 Nov 17.
Uncontrolled Keywords: *aneuploidy *cell cycle *chemotherapy resistance *cisplatin *paclitaxel have not collaborated directly on this project.
CSHL Authors:
Communities: CSHL labs > Sheltzer lab
Depositing User: Matthew Dunn
Date: 1 December 2020
Date Deposited: 19 Feb 2021 19:48
Last Modified: 19 Feb 2021 19:48
PMCID: PMC7720170
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