The role of chromosomal instability in therapy response of colorectal cancer

Abstract

Chromosomal instability (CIN) represents a major hallmark of cancer and is defined as the perpetual gain or loss of whole chromosomes during mitotic cell division. It is thought that CIN can drive tumor cell evolution by contributing to the generation of genetic heterogeneity in cancer. Importantly, tumor evolution might also fuel therapy resistance, a major problem for cancer patients in the clinic. However, whether CIN contributes directly to the generation of therapy resistance is unclear. So far it was not possible to systematically investigate the role of CIN and perpetual mitotic chromosome missegregation for the development of therapy resistance due to the fact that CIN could not be suppressed in chromosomally instable cancer cells. However, most recently, our lab has established means to correct an important molecular trigger for CIN in colorectal cancer (CRC) cells, namely increased microtubule dynamics during mitosis. In this way, it became possible to suppress chromosome missegregation and the evolvement of aneuploidy in otherwise chromosomally instable CRC cells. This now opens the possibility to investigate the role of CIN in therapy response, which was the aim of this study. I used various cell systems to compare the therapy response towards commonly used chemotherapeutic drugs in isogenic CIN and non-CIN cells. These include chromosomally instable CRC cells, in which CIN was suppressed by treatment with low doses of Taxol or by partial suppression of the microtubule polymerase chTOG/CKAP5. In addition, CIN was induced in chromosomally stable CRC cells by Aphidicolin treatment mediated replication stress or by inhibition of the mitotic spindle assembly checkpoint kinase Mps1. CIN and non-CIN cells were treated with Oxaliplatin, Cisplatin, 5-FU, Adriamycin, and Irinotecan. I found an increased resistance towards Oxaliplatin only in CIN cells with CHK2 deficiency. Other CIN cells (e.g. SW620, chromosomally stable HCT116 cells treated by Aphidicolin or MPS1-IN-3) did not show any response differences compared with non-CIN cells. These results might indicate the CIN phenotype per se does not confer drug resistance, but loss of CHK2 function itself might contribute to the drug resistance.