Suppression of Chromosome Instability Limits Acquired Drug Resistance

Abstract

Abstract Numerical chromosome instability, or nCIN, defined as the high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. nCIN has been shown to promote intratumor heterogeneity and corresponds with tumor aggressiveness, drug resistance, and tumor relapse. Although increased nCIN has been shown to promote the acquisition of genomic changes responsible for drug resistance, the potential to modulate nCIN in a therapeutic manner has not been well explored. Here we assess the role of nCIN in the acquisition of drug resistance in non–small cell lung cancer. We show that the generation of whole chromosome segregation errors in non–small cell lung cancer cells is sensitive to manipulation of microtubule dynamics and that enhancement of chromosome cohesion strongly suppresses nCIN and reduces intratumor heterogeneity. We demonstrate that suppression of nCIN has no impact on non–small cell lung cancer cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of nCIN alters the timing and molecular mechanisms that drive acquired drug resistance. These findings suggest mechanisms to suppress nCIN may serve as effective cotherapies to limit tumor evolution and sustain drug response.