Investigation into mechanisms of treatment resistance and heterogeneity in breast cancer and acute promyelocytic leukemia

Abstract

Treatment failure remains a leading contributor to cancer related death despite considerable advances in detection and treatment approaches. Several factors contribute to treatment failure including the high degree of tumor heterogeneity across patient populations and within individual patient tumors. While this heterogeneity can present an obstacle to successful treatment, it can provide new possibilities for personalized approaches to target resistant cancers and achieve better outcomes. This can be achieved through predicting patient response to different drugs to determine which treatment would be most effective as well as determining resistance mechanisms so that treatment strategies can be tailored to avoid these mechanisms. In this body of work, we utilized breast cancer and acute promyelocytic leukemia (APL) models to investigate resistance mechanisms associated with different therapies and the potential effect of using combination therapy to reduce resistance and enhance treatment outcome. Cancer stem cells (CSCs) are a source of tumor heterogeneity and facilitate tumor initiation and progression. To determine the role of different breast CSCs in the interplay with the immune system, we analyzed the differential expression of immune genes in the Aldefluor+ and CD44+CD24- breast CSCs and demonstrated that Aldefluor+ cells silence a key antigen presentation gene leading to their enhanced survival under immune pressure. Next, I applied a genome-wide shRNA screen to identify potential mediators of paclitaxel resistance in breast cancer, which is a common problem in the treatment of the cancer. This led to the identification of B cell lymphoma 6 (BCL6) as a contributor to paclitaxel resistance. I demonstrated enhanced tumor growth suppression in breast tumors treated with a BCL6 inhibitor and paclitaxel, suggesting a potential combination therapy that could be used overcome treatment resistance in breast cancer patients. Finally, I investigated the lasting benefits of combination treatment all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) treatment in APL cells. Only combination therapy was able to induce sustained demethylation and expression of target genes and in turn lasting changes in differentiation. Together, these studies highlight the importance of the studying heterogenous populations of tumors and mechanisms of resistance to inform strategies for combination treatments and improve patient outcomes.