Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division

John Michael Replogle, Wen Zhou, Adrianna E. Amaro, James M. McFarland, Mariana Villalobos-Ortiz, Jeremy Ryan, Anthony Letai, Omer Yilmaz, Jason Sheltzer, Stephen J. Lippard, Uri Ben-David, Angelika Amon

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)30566-30576
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number48
Early online date17 Nov 2020
DOIs
StatePublished - 1 Dec 2020

Keywords

  • Aneuploidy
  • Cell cycle
  • Chemotherapy resistance
  • Cisplatin
  • Paclitaxel

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