Suppression of Chromosome Instability Limits Acquired Drug Resistance

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 intra-tumor heterogeneity and corresponds with tumor aggressiveness, drug resistance and tumor relapse. While 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 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 intra-tumor 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 co-therapies to limit tumor evolution and sustain drug response.

Microtubule poleward flux as a target for modifying chromosome segregation errors

“…To explore our hypothesis, we used human non-transformed hTERT-immortalized retinal pigment epithelium cells (RPE-1), which we depleted of KIF18A because this depletion leads to chromosome misalignment (Garcia et al, 2002; Mayr et al, 2007; Stumpff et al, 2012, 2008; West et al, 2002; Zhu et al, 2005), occurrence of lagging chromosomes and micronuclei (Fonseca et al, 2019; Garcia et al, 2002; Stumpff et al, 2008; West et al, 2002), and excessively fast poleward flux of k-fibers (Risteski et al, 2022). To test whether lagging chromosomes and micronuclei in this system can be rescued by additional treatments, we used three mechanistically independent approaches: (i) we treated KIF18A-depleted cells with a low dose of paclitaxel (taxol), a treatment that partially rescues mitotic errors in cancer cells with increased microtubule dynamics (Crowley et al, 2022; Tamura et al, 2020); (ii) we co-depleted HAUS8, a subunit of the augmin complex, because this co-depletion rescues chromosome misalignment of KIF18A-depleted cells (Risteski et al, 2022); (iii) we co-depleted NuMA, which regulates the poleward flux of k-fibers (Risteski et al, 2022) ( Fig. 1A ; Supplementary Fig.…”

“…Passages were limited to a maximum of 8–10 weeks (∼10 passages). 2 h prior to live cell imaging or fixation, cells were subjected to a low dose of paclitaxel (taxol; National Cancer Institute), specifically 2 nM (Crowley et al, 2022; Tamura et al, 2020).…”