Targeting SMARCA2 in SMARCA4-deficient lung cancers in vivo - PROJECT SUMMARY/ABSTRACT Genomic alterations in SMARCA4, which encodes for the ATPase subunit of SWI/SNF chromatin remodeling complexes, are found in ~10% of non-small cell lung cancers (~20,000 new cases in the US for 2024), particularly in lung adenocarcinomas (LUAD). SMARCA4 alterations are strongly associated with metastasis, inferior responses to targeted therapies, and poor overall survival. We and others have shown that SMARCA4 is a bona fide lung tumor suppressor as its loss-of-function promotes malignant transformation, tumor progression, and metastasis. However, SMARCA4-altered LUAD currently lacks effective therapeutic strategies. SMARCA2, a SWI/SNF subunit that compensates for SMARCA4 function in its absence, is a leading therapeutic target for SMARCA4-deficient lung cancer. Genetic disruption of SMARCA2 inhibits the proliferation of cancer cells deficient in SMARCA4 function, but not of cells with intact SMARCA4. These findings led to the development of selective proteolysis targeting chimeras (PROTACs), e.g. degraders, for SMARCA2. However, in vivo studies investigating the mechanistic impact of SMARCA2 degradation on tumor progression are largely missing. This is an urgent unmet need because SWI/SNF complexes have highly dynamic epigenetic functions that are dependent on cellular and tissue context. I have developed genetically engineered mouse models (GEMMs) that faithfully capture the pathologic and molecular features of human SMARCA4-deficient LUAD, and extensively characterized the epigenetic states that arise in the absence of SMARCA4 during tumor evolution. These GEMMs provide a powerful preclinical system to mechanistically evaluate SMARCA2 degradation as a therapeutic approach and understand its impact on SWI/SNF function, cell state, and lung cancer progression. Our central hypothesis is that SMARCA4 loss results in distinct cell-intrinsic molecular features and cell-extrinsic alterations in the tumor microenvironment that dictate the responses to SMARCA2 degradation in vivo. In Aim 1, we will assess the effects of SMARCA2 degradation on SMARCA4-deficient lung cancer progression by treating our SMARCA4-deficient LUAD GEMMs with selective and potent SMARCA2 degraders and measuring efficacy and cell state changes that arise upon treatment. In Aim 2, we will determine the mechanisms that underlie the synthetic lethal relationship between SMARCA2 and SMARCA4 by mapping and integrating SWI/SNF activity, chromatin state, and transcription in tumor-derived cell lines from our GEMMs and by performing targeted genetic screens to identify persistence/resistance mechanisms. In Aim 3, we will harness the tumor immune microenvironment to develop effective combinatorial approaches to target SMARCA4-deficient LUAD and leverage patient samples to identify the molecular and cellular features of patients that may benefit from combination treatments. Our studies will provide a comprehensive understanding of SMARCA2 as a therapeutic target in SMARCA4-deficient LUAD, elucidate potential persistence/resistance mechanisms, and identify the most effective and clinically translatable combination approaches for this lethal molecular subtype of lung cancer.
