A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.

RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Unlabelled: Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007.

Opposing Roles of Mutations in Human Prostate and Endometrial Cancers.

Purpose: Recurrent gene mutations in speckle-type POZ protein (), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized mutations in these cancers and explored their association with molecular and immune signatures and patient outcomes.

Methods: There were 7,398 prostate cancer and 19,188 endometrial cancer samples analyzed for clinical and molecular profiles at Caris Life Sciences.

Suppression of Colon Tumorigenesis in Mutant Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin.

Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10.

Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS.

Approximately 30% of human cancers harbor a gain-in-function mutation in the RAS gene, resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS-mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS-driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand-1, reducing the expression of major histocompatibility complex molecules that present antigens to T-lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid-derived suppressor cells, regulatory T-cells, and cancer-associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T-cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells.

Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers.

Oncogenic mutations in genes result in the elevation of cellular active RAS protein levels and increased signal propagation through downstream pathways that drive tumor cell proliferation and survival. These gain-of-function mutations drive over 30% of all human cancers, presenting promising therapeutic potential for RAS inhibitors. However, many have deemed RAS "undruggable" after nearly 40 years of failed drug discovery campaigns aimed at identifying a RAS inhibitor with clinical activity.

Phenotypic differences between the sexes in the sexually plastic mangrove rivulus fish (Kryptolebias marmoratus).

To maximize reproductive success, many animal species have evolved functional sex change. Theory predicts that transitions between sexes should occur when the fitness payoff of the current sex is exceeded by the fitness payoff of the opposite sex. We examined phenotypic differences between the sexes in a sex-changing vertebrate, the mangrove rivulus fish (Kryptolebias marmoratus), to elucidate potential factors that might drive the 'decision' to switch sex.