Abstract 2186: Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance

Abstract

Abstract The breast tumor heterogeneity and development of drug resistance has become a challenge for anti-cancer therapy. Tumor cells acquire resistance due to intra-tumor heterogeneity imposed by epithelial to mesenchymal transition. The drugs which target epithelial cells may fail to target mesenchymal and the intermediate phenotypes due to which the cancer cells acquire drug resistance. This concept provoked us to understand the phenotypic diversity among the tumor heterogeneity which might lead to drug resistance. Hence the aim of our study is to identify the mechanisms of anti-cancer drug resistance which would ultimately help in identification of new clinical targets. Treatment of breast cancer cell lines MCF7 and MDA MB 231 with Doxorubicin showed a loss of epithelial markers and gain of mesenchymal markers in MCF7 cells, and vice versa in MDA MB 231 cells, thereby shifting them into an intermediate phenotype. Moreover, Doxorubicin treatment of MDA MB 231-Nanog stable cells led to an increase in Nanog positive cells confirming that the treatment-induced increase in stemness property of cancer cells. We predict that phosphoproteomic dataset of the anti-cancer drug-resistant cells let us analyze the possible molecular players involved in the phenotypic switch and hence drug resistance (work in progress). Thus, our current data suggest that the anti-cancer therapy induces cancer cells to undergo a phenotypic switch and increases the stemness property which might be responsible to gain resistance. Identification of the critical regulators of the phenotypic switch by phosphoproteomics analysis is likely to help us investigate the possible mechanisms underlying anti-cancer drug resistance. Previous reports also suggest that conventional therapies fail to eliminate cancer stem cells thereby allowing tumor relapse. These results suggest that understanding the protein abundance and phosphorylation state of key signaling molecules would elucidate specific signaling interactions or/and pathways differentially active in drug-resistant tumors would help us predict novel kinases, and hence identify drug targets. Citation Format: Santhalakshmi Ranganathan, Annapoorni Rangarajan. Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2186.