Chromosomal Instability Confers Intrinsic Multidrug Resistance

TLDR

Aneuploidy and chromosomal instability in solid tumors are linked to poor prognosis, drug resistance, and tumor relapse. The study aims to identify therapeutic agents that target the karyotypic complexity of CIN tumors. Using CIN+ and CIN- colorectal cancer cell lines, the authors screened a library of kinase inhibitors targeting signal transduction, cell cycle, and receptor pathways to find treatments that limit CIN tumor growth. CIN+ colorectal cancer cells exhibit intrinsic multidrug resistance independent of mutation status or proliferation, and CIN+ status predicts poorer progression‑free survival, indicating that CIN should be considered when designing clinical trials. Cancer Res 71(5):1858‑70; © 2011 AACR.

Abstract

Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN+) or diploid/near-diploid (CIN-), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN+ cell lines displayed significant intrinsic multidrug resistance compared with CIN- cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN+ displayed multidrug resistance relative to their CIN- parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression-free or disease-free survival relative to patients with CIN- disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity. Cancer Res; 71(5); 1858-70. (c) 2011 AACR.