Impact of recurrent genetic alterations on SCLC subtypes and therapeutic response

Project Summary Small cell lung cancer (SCLC) is a highly aggressive malignancy with high heterogeneity and few available treatment options. SCLC cells are of highly plastic enabling them to adapt and change characteristics in response to chemotherapy and radiation therapy. This project aims to interrogate therapeutic responses that targeting replication stress, hallmark of SCLC. Specifically, we will establish novel SCLC animal models, with co-mutations that identified in the clinic responsible for the development, progression, or drug resistance. To do that, we will use establish SCLC lines with P53 and RB1 mutation, two most common mutations found in SCLC that serve as intrinsic factor responsible for replication stress, and introduce co-mutations including MYC, KMT2D, and/or the STK11/PTEN etc. We hypothesized that c-MYC, YAP1, PTEN, STK11, KMT2D, p130 dysregulation may contribute to SCLC heterogeneity, replication stress, and will affect tumor growth. We will evaluate in these models, the impact of co-mutations toward the treatment of CDK2 and/or PARP inhibitors. In addition, we will further delineate, the cancer cell intrinsic versus extrinsic effect upon drug treatment using state-of-art immune competent SCLC models. Finally, we will further explore the possibility of combinational treatment of targeted drugs with immunotherapy drugs in SCLC models with different co- mutations. To test our hypotheses, we propose the following interrelated Specific Aims: (1) To investigate the impact of the co-mutations on SCLC plasticity and transcriptional subtypes of SCLC; (2) To evaluate the impact of co-mutations on the responses to CDK2 and PARP inhibition responses in SCLC; and (3) To elucidate the impact of co-mutations on the SCLC tumor immune microenvironment (TIM) and sensitivity to immunotherapeutic combinations. Project 4 is integrated cohesively with Projects 1, 2 and 3, and Cores A, B and C, permitting innovative and synergistic approaches and quick breakthroughs in moving basic science discoveries to translational therapeutic strategies. IMPACT: By investigating a new scientific direction in this P01 through pioneering work on the co-genetic alterations and pre-clinical studies, we will develop new mechanistic insights into biological mechanisms of SCLC replication stress that can be translated into clinically relevant therapies for patients.