Of the several subtypes of breast cancer, the hormone-refractory `triple negative breast cancer (TNBC)' (indicating lack of estrogen, progesterone and HER2neu receptor expression) are less responsive to treatment and have a much worse prognosis as compared to receptor-positive breast cancer. The five-year survival rate for TNBC is 77% versus 93% of women with other types of breast cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are emerging as promising therapeutics for the treatment of TNBC in a clinical setting. However, acquired resistance to PARPi presents a pervasive barrier to effective treatment and the underlying mechanisms of resistance are poorly understood which has substantiated a need for further investigation in the mechanisms of resistance to PARPi. Autophagy is a self-digestive process, wherein in response to environmental stress, misfolded and aggregated proteins are sequestered and delivered to the lysosome for subsequent degradation and recycling. These recycled biomolecules resulting from autophagy, provide the rapidly growing tumor cells a steady stream of nutrients. Many clinical studies have implemented an autophagy inhibitor (AI) in combination with other drugs to elicit effective cell death in multiple cancers including breast cancer. Autophagy inhibition has also shown to reverse the resistant phenotype of several cancers. Perplexingly, while autophagy inhibition in combination with other chemotherapeutic agents has shown promising therapeutic potential in TNBCs, no major advances have been made in understanding the molecular mechanisms underlying autophagy in resistance to PARPi in TNBCs. Within the scope of this proposal, we address an unmet pressing need to evaluate the synergistic effect of AI in combination with PARPi in the reversal of TNBC resistance to PARPi. Current research proposal is aimed at improving our understanding of the molecular mechanisms of autophagy-apoptosis crosstalk in conferring resistance to PARPi in TNBC. Our main objectives are: 1) Using a combinatorial treatment of autophagy inhibitor (AI) with PARPi, characterize the modulation of apoptotic and autophagic markers in cell death and 2) Identify and evaluate the important rate-limiting factors such as LC3, Akt and oxidative stress involved in modulating autophagy and apoptosis in the resistant TNBC model. The results and contributions of this study will be significant and innovative as they can provide novel avenues for pharmacological intervention in overcoming resistance to PARPi and change the treatment paradigm for this subset of breast cancer with poor prognosis and limited treatment options.
The overarching challenge of this proposal is to identify the molecular factors that confer resistance to PARP inhibitors in Triple Negative Breast Cancer (TNBC). To this effect, we have developed in vitro TNBC models that have acquired resistance to PARP- inhibitor and show elevated levels of autophagy. We aim to use a combinatorial treatment of autophagy inhibitor and PARP-inhibitor to achieve reversal of the resistant phenotype and re-sensitize the cells to apoptotic stimuli. The preclinical findings of this study will be significant, as identifying these deregulated proteins will give molecular leads for improved therapy resulting in effective and sustained cell death using PARP- inhibitors in TNBC.
