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Proc Natl Acad Sci U S A DOI:10.1073/pnas.2009506117

Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division.

Publication TypeJournal Article
Year of Publication2020
AuthorsReplogle, JMichael, Zhou, W, Amaro, AE, McFarland, JM, Villalobos-Ortiz, M, Ryan, J, Letai, A, Yilmaz, O, Sheltzer, J, Lippard, SJ, Ben-David, U, Amon, A
JournalProc Natl Acad Sci U S A
Volume117
Issue48
Pages30566-30576
Date Published2020 Dec 01
ISSN1091-6490
Abstract

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.

DOI10.1073/pnas.2009506117
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33203674?dopt=Abstract

Alternate JournalProc Natl Acad Sci U S A
PubMed ID33203674