Oncogenic activation of RAS genes via point mutations occurs in 20%–30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that rigosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after curative treatment of early-stage HCC tumor, the carcinogenic microenvironment persists in the remnant diseased liver and supports the development of de novo HCC tumors (de novo HCC recurrence). Therefore, prevention of HCC development in patients at risk of not only first-primary but also second-primary HCC tumors is theoretically the most impactful strategy to improve patient prognosis. However, no such therapy has been established to date. One major challenge is the identification of clinically relevant targets that can be achieved by utilizing the reverse-engineering strategy of chemoprevention discovery, which integrates omics information from clinical cohorts with completed follow-up for cancer development. Clinical and experimental studies have suggested etiology-specific and generic candidate HCC chemoprevention strategies, including statins, antidiabetic drugs, selective molecular targeted agents, and dietary and nutritional substances. Clinical testing of the candidate compounds can be cost-effectively performed by combining it with HCC risk biomarker evaluation to specify the target patient population most likely to benefit from the therapy. Nontoxic, generic agents will have broad clinical applicability across the diverse HCC etiologies and clinical contexts and are expected to substantially improve the still dismal prognosis of HCC.

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