Chromosomal instability and aneuploidy as causes of cancer drug resistance.

High levels of aneuploidy and chromosomal instability (CIN) are correlated with poor patient outcomes, though the mechanism(s) underlying this relationship have not been established. Recent evidence has demonstrated that chromosome copy number changes can function as point mutation-independent sources of drug resistance in cancer, which may partially explain this clinical association. CIN generates intratumoral heterogeneity in the form of gene dosage alterations, upon which the selective pressures induced by drug treatments can act. Thus, although CIN and aneuploidy impair cell fitness under most conditions, CIN can augment cellular adaptability, establishing CIN as a bet-hedging mechanism in tumor evolution. CIN may also endow cancers with unique vulnerabilities, which could be exploited therapeutically to achieve better patient outcomes.