Chromosomal instability determines taxane response

Abstract

Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these ''CIN-survival'' genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.chemotherapy ͉ drug resistance

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

“…Support for this strategy stems from observations that CIN is a predictor of favorable response to therapies that induce chromosome missegregation, particularly conventional DNAdamaging cytotoxic therapies. For instance, CIN correlates with sensitivity to platinumbased therapies in ovarian cancer (Swanton et al 2009), and in those with locally advanced rectal cancer, considerably elevated rates of chromosome missegregation are associated with a higher likelihood of pathologic response after treatment with radiation therapy and concurrent 5-fluorouracil (Zaki et al 2014). Consistent with this notion, in the pancancer analysis performed by Andor et al (2016), the negative impact of CIN on survival was abolished in the subset of patients who received DNA-damaging therapies (Fig.…”

“…Among colorectal cancer-derived cell lines, chromosomally unstable cells are more resistant to targeted kinase inhibition as compared with their chromosomally stable counterparts (Lee et al 2011). In patients with breast cancer, the presence of moderate CIN is associated with inferior prognosis and resistance to taxanes whereas extreme CIN is associated with improved survival and reduced tumor relapse after primary therapy (Swanton et al 2009;Roylance et al 2011;Jamal-Hanjani et al 2015). Furthermore, in a pancancer genomic analysis of intratumor heterogeneity, patients that had tumors in the middle quartiles of chromosome copy number variations were at a significantly greater risk for death compared with those with tumors in the lowest or highest quartiles of chromosome copy number variations (Andor et al 2016).…”

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

“…Even among susceptible cancers, the majority of patients eventually develop resistance. There are multiple pathways involved in acquired resistance to taxanes, including detoxification, alterations in tubulin dynamics, chromosomal instability, and antiapoptotic pathways (4)(5)(6)(7)(8)(9). Another common cause of resistance in cancer cells is the expression of ATP-dependent drug efflux pumps, such as P-glycoprotein (P-gp), also known as ABCB1, the product of the multidrug-resistance-1 gene (MDR1; reviewed in ref.…”

Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth

“…MDA-MB-468 was insensitive in our hands, despite being sensitive in the NCI-60 cell screen. This cell line is known for high genomic instability (25,26) and has been reported as EGFR-overexpressing as well as frankly triple-negative by some investigators. Sensitivity of this line to lapatinib has been found to be markedly lower than that of other more typically HER2-overexpressing cell lines (27).…”