Novel Pan-RAS Inhibitor ADT-007 Induces Tumor Regression in Mouse Models of GI Cancer

ABSTRACT Here we describe a novel class of pan-RAS inhibitor with highly potent and selective anticancer activity by killing cancer cells harboring mutations in RAS or with constitutively activated RAS resulting from mutations in upstream signaling components. A lead compound from this chemical family, ADT-007, binds RAS when in a nucleotide free transitional state to block loading of GTP, thereby interfering with RAS activation and disruption of binding to effectors such as RAF and PI3K to suppress MAPK and AKT signaling. ADT-007 potently inhibits the growth of cultured human and murine cancer cell lines with single-digit nM IC50 values irrespective of specific RAS isozyme or mutational codon. ADT-007 also inhibits tumor growth in vivo through inhibition of RAS-MAPK signaling in syngeneic, immune competent and xenogeneic, immune deficient mouse models of colon and pancreatic cancer. In RAG 1 -/- mice the activity of ADT-007 is partially inhibited indicating a role for the adaptive immune system in ADT-007-mediated tumor growth inhibition. Ex vivo analyses of tumor infiltrating leukocytes, reveals that ADT-007 enhances T cell functions in the pancreatic and colorectal tumor immune microenvironment. SIGNIFICANCE ADT-007 represents a 1st-in-class pan-RAS inhibitor with broad anticancer activity across all RAS driven cancers and unique chemical selectivity to allow normal cells to be spared from pan-RAS inhibition. ADT-007 also has the potential to modulate the adaptive immune response in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDA). These data support future clinical trials of an orally bioavailable prodrug of ADT-007 as a monotherapy for the treatment of patients with CRC or PDAC regardless of the underlying mutation or in combination with immunotherapy.