Emerging Therapeutic Directions for Cancers With Mutations Within the Complex Proteins Associated With Set1 Family: A Systemic Review

PURPOSE Mutations within the Complex Proteins Associated With Set1 (COMPASS) family of histone lysine methyltransferases are frequently found in many human diseases including cancer. Increasingly, these common mutations are being investigated as clinically relevant targets for therapeutic advantage in cancer. We conducted a systemic review of published studies to evaluate the landscape of COMPASS mutations in cancer from a clinical viewpoint. METHODS We performed a comprehensive literature review to identify both clinical and relevant preclinical studies analyzing cancer therapies or biomarkers in relation to COMPASS family mutations. Studies were identified systemically using electronic databases. RESULTS A total of 50 clinical and preclinical studies were included in this systemic review. The search identified majority phase I or II ongoing clinical trials of menin-MLL inhibitors in patients with leukemia and other completed phase III clinical trials targeting MLL1-rearranged AML or ALL. Preliminary studies targeting solid tumors with MLL4 and cofactor UTX alteration were identified. CONCLUSION Alterations within the COMPASS family of proteins are frequently found in cancers. These gene mutations have prognostic and predictive implications. Despite notable recent efforts to target these alterations, only therapeutic inhibition of two COMPASS family members MLL1 (encoded by KMT2A gene) and MLL4 (encoded by KMT2D gene) has translated to clinical studies. Identification of solid tumors with pathogenic MLL1 fusions, which are disrupted by menin inhibition, raises a possibility of evaluating current therapeutic agents being studied in MLL1-rearranged leukemias, in a broad range of malignancies. Studies investigating therapeutic targeting of MLL2, MLL3, SETD1A, and SETD1B are particularly lacking. There is a pressing need to expand novel precision-based strategies for oncodriver proteins within the COMPASS family.