Grant: Project Grant

SMARCA4 is a critical member of a large protein complex that binds to DNA and regulates the accessibility of DNA, thereby controlling the expression of genetic information stored in DNA during normal development. Inactivating SMARCA4 mutations occur in a highly aggressive subset of cancers originated from the ovary, lung, and other organs. These cancers remain hard to treat as SMARCA4 loss is not directly targetable, and they rarely harbor known druggable cancer-promoting genetic mutations and are resistant to conventional chemotherapies. We have recently found that SMARCA4-mutant cancer cells depend on the enzymatic activity of p300, a protein that also controls gene expression in part through the interaction with SMARCA4 to approach DNA. In this proposed work, we aim to elucidate the mechanism underlying the dependency on p300 in SMARCA4-mutant cancer cells; we will also evaluate the potential clinical utility of targeting p300 with a selective inhibitor in ovarian and lung cancers with SMARCA4-loss. We propose that SMARCA4-loss may alter the DNA targeting specificity of p300 in these cancer cells to promote the expression of a novel set of genes critical for tumor development and maintenance, resulting in a vulnerability for therapeutic targeting. We will test this hypothesis by performing systematic and complementary biochemical, histopathological and drug testing experiments in a variety of model systems, including cell culture, primary patient tumors, and mouse models of cancer. Our proposed study will not only shed light on the molecular pathogenesis of SMARCA4-mutant cancers, but also validate the potential of targeting p300 dependency with available therapeutic agents to treat these aggressive cancer types.