Enhancing Triple Negative Breast Cancer Response to Immune Checkpoint Inhibitor Therapy via Targeted Therapies
Bullock, Kennady Kara
0000-0002-9773-3512
:
2024-06-10
Abstract
Triple-negative breast cancer (TNBC) is a heterogenous and challenging to treat subtype of breast cancer characterized by lack of HER2 amplification and lack of expression of the hormone receptors, ER and PR. The introduction of anti-PD-1 to the clinical management of TNBC represents a breakthrough for a disease whose treatment has long relied on the standards of chemotherapy and surgery. Nevertheless, few TNBC patients achieve a durable remission in response to anti-PD-1, and there is a need to develop strategies to maximize the potential benefit of immune checkpoint inhibition (ICI) for TNBC patients. Herein, I explore pan-AKT inhibition as a strategy to enhance ICI response. Using four TNBC-like cell lines and corresponding orthotopic mouse tumor models, I found that hyperactivity of the PI3K pathway as evidenced by basal pAKT levels associated with response to an ATP-competitive pan-AKT inhibitor, while RAS/MAPK/ERK mutations could override the response of PI3K mutant tumors to AKT inhibition. I also developed a high-throughput screening platform designed to identify compounds that enhance T-cell mediated cytotoxicity. This assay was used to screen a library of 488 Anti-Cancer compounds. Four cytotoxic chemotherapy agents were chosen for detailed mechanistic follow-up and were found to have dose-dependent immunostimulatory properties. Overall, this work provides insight into how we might best utilize existing targeted and chemotherapies to enhance responses to ICI in TNBC.