Pan-RAS inhibitors and polo-like kinase 1: promising targets in colorectal cancer

Abstract

RAS is an oncogene that is commonly mutated in colorectal cancer (CRC). It has been considered a negative feature both due to its impact on prognosis and due to the shallow interface of oncogenic Ras for therapeutic targeting. Newer pan-Ras inhibitor strategies include improved direct targeting of RAS, blockade of downstream effectors, immunotherapy approaches, and even the inclusion of anti-EGFR drugs. Polo-like Kinase 1 (PLK1) is a serine/threonine protein kinase that controls multiple aspects of the cell-cycle. It is upregulated in CRC and has become an important therapeutic target in KRAS mutant CRC, with several PLK1 inhibitors currently in various phases of development and testing. As with other targeted therapies, resistance remains a problem and combination strategies may be beneficial. This review discusses pan-RAS inhibitors and PLK1 in the context of CRC. It discusses RAS' many roles, its associated pathways and relationship to cancer progression, the current status of existing inhibitors, and future strategies for targeting in cancer therapy. The wide-ranging impacts of RAS provide a basis to better understand and fight against CRC.

Fig. 1

Overview of Ras pathways.

Fig. 2

The PLK1 structure includes two functional polo-box domains (PBDs) at the C-terminal and the kinase domain at the N-terminal.