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. As a result, despite the growing success of checkpoint immunotherapy, many patients with RAS-driven tumors experience resistance to therapy and poor clinical outcomes. Therefore, RAS inhibitors in development have the potential to weaken cancer cell immune evasion and enhance the antitumor immune response to improve survival of patients with RAS-driven cancers. This review highlights the potential of RAS inhibitors to enhance or broaden the anticancer activity of currently available checkpoint immunotherapy.
Oncogenic mutations in RAS 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. Here we review RAS nucleotide cycling and the opportunities that RAS biochemistry presents for developing novel RAS inhibitory compounds. Additionally, compounds that have been identified to inhibit RAS by exploiting various aspects of RAS biology and biochemistry will be covered. Our current understanding of the biochemical properties of RAS, along with reports of direct-binding inhibitors, both provide insight on viable strategies for the discovery of novel clinical candidates with RAS inhibitory activity.
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 sexchanging vertebrate, the mangrove rivulus fish (Kryptolebias marmoratus), to elucidate potential factors that might drive the 'decision' to switch sex. Rivulus populations consist of self-fertilizing hermaphrodites and males. Hermaphrodites transition into males under certain environmental conditions, affording us the opportunity to generate 40 hermaphrodite-male pairs where, within a pair, individuals possessed identical genotypes despite being different sexes. We quantified steroid hormone levels, behavior (aggression and risk taking), metabolism and morphology (organ masses). We found that hermaphrodites were more aggressive and risk averse, and had higher maximum metabolic rates and larger gonadosomatic indices. Males had higher steroid hormone levels and showed correlations among hormones that hermaphrodites lacked. Males also had greater total mass and somatic body mass and possessed considerable fat stores. Our findings suggest that there are major differences between the sexes in energy allocation, with hermaphrodites exhibiting elevated maximum metabolic rates, and showing evidence of favoring investments in reproductive tissues over somatic growth. Our study serves as the foundation for future research investigating how environmental challenges affect both physiology and reproductive investment and, ultimately, how these changes dictate the transition between sexes.
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