Abstract 2951: A comprehensive analysis of proteins involved in innate and acquired resistance to molecularly-targeted drugs in breast cancer cells

Abstract

Abstract Cancer is the second leading cause of death among Americans, and despite advances in diagnosis, new technologies for early detection, and development of potent molecularly-targeted drugs, survival rates in advanced disease have not been improving at desired rates. Perseverance of cancer cells seem to rely both on their significant heterogeneity at the onset of treatment, and the inherent plasticity (genetic instability) to adopt to environmental conditions and exogenous agents. Cancer is known as a heterogeneous disease. In fact, extensive genetic diversity has been revealed not only between different types of cancer, but also within a single tumor (as diversity in the expression of protein biomarkers). This intra-tumor heterogeneity could be a major obstacle in cancer treatment due to a wide range of responsivity to any specific anticancer agent. This study aims to analyze the heterogeneity and plasticity among a small panel of breast cancer cell lines as a reaction to exposure to a variety of molecularly-targeted agents, which could lead us to identification of the proteins that play major roles in drug resistance in cancer cells. After initial evaluation of the LC50, we exposed five different breast cancer cell lines to high doses of erlotinib (selective ErbB1/EGFR-inhibitor), vemurafenib (pan Raf inhibitor), everolimus (selective mTORC1 inhibitor), and ruxolitinib (pan JAK inhibitor), an collected the survivors. Using an in-house designed microarray and real-time PCR analysis, we analyzed the protein expression profile of the survivors compared to the untreated population, which revealed proteins involved in innate resistance and the heterogeneity among the population. In an alternative approach, we exposed the cells to gradually increasing doses of these selected agents, affording the cells the opportunity to adapt to the treatment. The resistant cells were then analyzed in a similar fashion to reveal proteins involved in acquired resistance. Citation Format: Hamid Montazeri. A comprehensive analysis of proteins involved in innate and acquired resistance to molecularly-targeted drugs in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2951.