Abstract C50: Sensitivity of triple-negative breast cancer cell lines to cytotoxic and targeted agents as a function of molecular subtype

Abstract

Abstract Triple-negative breast cancer is a heterogeneous disease with no approved targeted therapies. The disease course is very aggressive, characterized by relapse within 3 years of treatment and metastases to the viscera, including the brain. The prognosis in the setting of distant metastases is grim, as median survival is less than one year. Recently, insight into the molecular complexity of TNBC was provided by gene expression analysis, which identified six unique subtypes with distinct gene ontologies that differ with respect to drug sensitivity. These subtypes, each enriched in unique molecular components and pathways, suggest target-based strategies for treatment. A multiplicity of targeted drugs has entered clinical trials for the potential treatment of TNBC, but no uncontested victor has emerged that can appreciably extend overall survival. For instance, one of the most promising experimental drugs is iniparib, which significantly improved outcomes in a Phase II clinical trial of metastatic TNBC when combined with carboplatin/gemcitabine; however, overall survival was still unacceptably short at ~1 year. Therefore, there remains a dire need to identify novel therapeutic modalities for TNBC. A promising research strategy towards this goal is to determine the differential sensitivities of the TNBC molecular subtypes to combinations of cytotoxic and targeted drugs. We are determining the responses of a panel of TNBC cell lines representing different molecular subtypes, including the basal-like 1 (HCC1143 and MDA-MB-468), basal-like 2 (HCC1806 and HCC70), immunomodulatory (HCC1187), mesenchymal stem-like (MDA-MB-436, MDA-MB-231, and MDA-MB-157), and luminal androgen receptor (MFM-223) subtypes, to variable doses of carboplatin, capecitabine, cyclophosphamide, docetaxel, and everolimus, used alone and in combination. These drugs were chosen because they target molecular regulators of prominent signaling pathways specific to certain TNBC molecular subtypes, so we expect to find that sensitivity to these drugs is a function of subtype. The results of this study will enable characterization of TNBC subtypes in finer detail and provide a preclinical framework for the development of subtype-dependent regimens for TNBC treatment. Citation Format: Heather Colley, Roopali Saxena, Angela Ogden, Guilherme Cantuaria, Michelle D. Reid, Xiaoxian (Bill) Li, Uma Krishnamurthy, Padmashree CG Rida, Ritu Aneja. Sensitivity of triple-negative breast cancer cell lines to cytotoxic and targeted agents as a function of molecular subtype. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C50.