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

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

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy

Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression. The pharmacological potential of targeting ABCC1, however, remained to be assessed. In this study, we investigated whether the blockade of ABCC1 affects prostate cancer cell proliferation using both in vitro and in vivo models. Our data demonstrate that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Collectively, these data identify ABCC1 as a novel and promising target in prostate cancer therapy