Abstract C50: Identification of secondary targets to enhance anthracycline-based therapy
Authors: Flores-Rozas Hernan , Mazu Tryphon , Freeman Miles D. , Miles Jana S. 
Published: May 2015

Breast cancer is the most common cancer in women worldwide. African-American women (AA) tend to have more aggressive breast cancers that present more frequently as estrogen receptor, progesterone receptor (PR) and HER2 negative which are referred to as “triple negative” breast cancers (TNBC). TNBC tumors carry worse prognoses and are harder to manage because they lack the molecular targets required for therapies. In patients suffering from TNBC cytotoxic agents such as anthracyclines are some of the few therapeutic alternatives. Anthracyclines are among the most common chemotherapeutic agents used to-date. Although effective, resistance to this agent usually develops in the course of treatment and serious dose-related toxicity, namely chronic cardio-toxicity, limits their use. To increase our knowledge of the pathways that protect cells from anthracyclines we carried out a genome-wide genetic screening in the eukaryotic model organism S. cerevisiae to identify gene defects that generate cells hypersensitive to doxorubicin. A total of 71 deletion strains displayed varying levels of sensitivity to anthracyclines. Major pathways were represented by multiple genes, including homologous recombination/DNA repair, the heat-shock response, chromatin remodeling and aminoacid metabolism. To further investigate the mechanisms that render cells hypersensitive to anthracyclines when genes of these pathways are inactivated, we determined the sensitivity of several mutants to a series of cytotoxic agents. Our findings indicate that inactivation of the heat-shock protein 40 encoded by the genes YDJ1 and ZUO1, as well as the heat-shock protein 70 encoded by the gene SSZ1, render cells highly sensitive to the toxicity of doxorubicin and cisplatin. In addition, deletion of chromatin remodeling factor SNF2 resulted in sensitivity to doxorubicin of 100,000-fold higher than wild type cells and it is also sensitive to daunorubicin, cisplatin, as well as to DNA alkylating agents, topoI inhibitor campthotecin or replication blocks from hydroxyurea. Interestingly, mutations of the HOM6 gene increases the accumulation of an aldehyde intermediate that synergizes with anthracyclines. Taken together, our data indicates that inactivation of any of these pathways can be targeted to hypersensitize cancer cells to cytotoxic agents to enhance chemotherapeutic efficacy in TNBC.

This project was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 2 G12 RR003020 and 8 G12 MD007582-28.

Citation Format: Hernan Flores-Rozas, Tryphon Mazu, Miles D. Freeman, Jana S. Miles. Identification of secondary targets to enhance anthracycline-based therapy. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C50. doi:10.1158/1538-7755.DISP13-C50