PI3K-gamma signaling as a therapeutic vulnerability of POU2F3+ small cell lung cancer

ABSTRACT Small cell lung cancer (SCLC) is a highly lethal and aggressive neuroendocrine tumor of the lung that is marked by early metastasis and resistance to therapies leading to a median survival of only ~12 months. Tumors typically respond to first-line platinum-based chemotherapy but rapidly develop resistance. Furthermore, only a small fraction of patients responds to recently-approved immunotherapies. SCLC comprises four molecular subtypes, including the POU2F3+ SCLC (SCLC-P) subtype, which transcriptionally mimics a pulmonary tuft cell and is associated with the worst overall survival. However, SCLC-P remains poorly understood and lacks targeted therapies. Thus, new therapeutic targets for SCLC, especially for SCLC-P, are critically needed. My preliminary data suggests that SCLC-P is dependent on PI3K signaling and through re-analysis of multiple mouse and human datasets that tuft cells and tuft-like cancers, including SCLC-P, surprisingly express PIK3CG (PI3K gamma isoform). PIK3CG expression was previously thought to be restricted to immune cells, primarily myeloid cells. Due to this lineage-restricted expression, in early-phase clinical trials, PIK3CG inhibitor IPI-549 has shown favorable tolerability and lacks the dose-restricting toxicities common to pan-PI3K inhibitors. Thus, we hypothesize that PIK3CG may be a clinically relevant vulnerability of the highly aggressive SCLC-P subtype. Preliminary data using both a small molecule inhibitor and a PROTAC demonstrate increased sensitivity to PIK3CG inhibition in SCLC-P. In this proposal, I will use genetic and pharmacologic approaches to determine if PIK3CG and its regulatory partner PIK3R5 are uniquely necessary for the SCLC-P subtype (Aim 1) and if PIK3CG inhibition in combination with chemotherapy is an effective therapy for SCLC-P in vivo (Aim 2). These data will reveal a potential new therapeutic target of SCLC-P that we expect to lead to a clinical trial on PIK3CG inhibition in SCLC. Trials have shown efficacy for PIK3CG inhibition in augmenting immunotherapy through targeting myeloid derived suppressor cells. Thus, PIK3CG inhibition may ultimately have the dual effect of targeting SCLC-P and enhancing immunotherapy, a first-line therapy for SCLC. Additionally, as PIK3CG is enriched across tuft cells and tuft-like cancers, we expect these findings to have implications for other cancers that take on a tuft-like state including prostate neuroendocrine cancer and olfactory neuroblastoma. The proposed research will provide unique training opportunities in cancer biology, targeted therapeutic development, and in vivo preclinical drug studies, which align closely with my training plan and career goals. The proposed research will occur over two additional years of training at Duke University School of Medicine in the laboratory of Dr. Trudy Oliver, followed by one additional year of clinical training.