Targeting eIF4A1 in drug-resistant breast cancer stem-like cells The overarching goal of this project is to delineate the regulatory mechanisms by which the helicase activity of eIF4A1 controls pluripotency TFs and ABC drug transporters and how this can be exploited to overcome drug resistance in metastatic TNBC. Currently, despite significant improvements in the survival rates of primary breast cancer patients, 90% of the mortality is due to chemoresistance from aggressive tumors leading to metastasis. Neoadjuvant hemotherapy (NACT) is the mainstay of treatment though poly ADP-ribose polymerase (PARP) inhibitors are available along with immunotherapy. The pathological complete response (pCR) is generally low in TNBC patients. Resistance to NACT and also to targeted therapy is mainly due to a small population of breast cancer stem-like cells (BCSCs) or tumor-initiating cells. BCSCs are intrinsically chemoresistant with high plasticity and self-renewal capability. Their proliferative and invasive capacity mediates tumorigenesis, immune evasion and metastasis. Acquired resistance to chemo- and immunotherapy also develops during treatment. Following such therapy, the bulk tumor cells die but BCSCs survive and constitute the minimal residual disease (MRD). The surviving pluripotent BCSCs can undergo multi-lineage differentiation and repopulate the entire heterogeneous tumor. This leads to tumor relapse which are more aggressive and highly metastatic in nature. Tumors with high expression of BCSC stemness markers (ALDH and CD44) demonstrate worst clinical outcomes in TNBC patients. Thus, there is an unmet need for identifying novel targets and strategically target BCSCs to overcome chemoresistance, eliminate MRD and achieve better pCR in metastatic TNBC (mTNBC). In this study, we propose to find the mechanisms by which the helicase activity of eIF4A1 regulates pluripotency, ABC transporters that contribute to chemoresistance. We propose in aim 1 to determine the role of the helicase activity of eIF4A1 in the regulation of pluripotency and ABC transporters in vitro. In aim2, we will determine the role of the helicase activity of eIF4A1 in the regulation of pluripotency and ABC transporters in vivo. In aim3 we propose to translate the findings in aim1 and 2 to preclinical PDX and CDX murine models. This will facilitate in developing novel combination therapies effective in mTNBC and hopefully translate it into human phase I trial.

Drug resistance and minimal residual disease in triple-negative breast cancer (TNBC) leads to aggressive tumors and metastasis leading to many fatalities. Altered tumor protein profile in TNBC contributes to therapy resistance in the clinic. The proposal outlines a strategy to identify the mechanisms through which eIF4A1 might facilitate drug resistance program in TNBC Finally, we outline strategies to overcome chemoresistance by co-targeting eIF4A1 and its downstream translational targets in breast cancer stem-like cells (BCSCs) and bulk tumor cells in metastatic TNBC.