Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division

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.

Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in Candida albicans

“…In C. albicans , as well as in many other organisms, aneuploidy is a prevalent strategy of stress adaptation ( 59 , 60 ; reviewed in references 61 – 64 ). Specifically, aneuploidy is often a rapid mechanism of adaption to antifungal stress ( 11 – 13 , 16 , 17 ; reviewed in reference 65 ) and also facilitates adaptation to other stresses in vitro , e.g., alternative carbon sources ( 66 – 68 ; reviewed in reference 69 ), and in vivo , e.g., passage in mouse blood ( 70 ), the oral cavity ( 71 , 72 ), and the gastrointestinal tract ( 73 ).…”

Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

“…Because of this, there are several ongoing efforts concentrated on understanding the contribution of cell-intrinsic factors-such as genetic alterations and epigenetic changes-as well as cell-extrinsic stimuli-such as cytokines and growth factors-as major players responsible for drug resistance (Vasan et al, 2019). Recent studies have identified an increased resistance of aneuploid cancer cell lines to multiple chemotherapies and to drugs in general (Cohen-Sharir et al, 2021;Replogle et al, 2020). However, very little is known about how and why aneuploidy and the ensuing genomic instability affects the therapeutic outcome.…”

Extensive protein dosage compensation in aneuploid human cancers

“…A majority of cancers have chromosome arm gains or losses 1 , a state called aneuploidy. Aneuploidy has been shown to contribute to tumor evolution [2][3][4] , drug resistance 3,[5][6][7][8][9] , and metastatic dissemination [10][11][12] . High levels of aneuploidy are also associated with poor patient survival 3,[13][14][15][16][17][18] .…”