PLK1 and its role in the evolving landscape of KRAS-mutated colorectal cancer

Rat sarcoma virus (RAS) consists a family of membranebound proteins with GTPase activity.They derive their name from the RAS and initial studies were carried out in the 1960s by Drs.Jennifer Harvey and Werner H. Kirsten, where they induced sarcomas in rodents using a murine leukemogenic virus preparation (1,2).The RAS family of proteins includes three GTPases: Harvey (HRAS), Kristen (KRAS) and neuroblastoma (NRAS) homologues encoded by the corresponding RAS genes.Under normal circumstances, RAS proteins play a central and interconnected role in regulating intracellular signalling, intrinsic to normal physiological cellular proliferation, growth and survival through the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signalling pathway (Figure 1).Mutations in the RAS-RAF-MEK-ERK pathway genes can result in activation of the pathway leading to unchecked cellular proliferation and oncogenesis.Dysregulation of this pathway occurs very commonly in cancers, with somatic mutations in KRAS being found in roughly 30% of all cancers globally, including in lung (30%), colorectal cancer (CRC) (45%), cholangiocarcinoma (15-50%) and pancreatic cancer (>80%) (3).Owing to the complexity and interconnectedness of the pathway, KRAS and other RAS isoforms were long considered to be "undruggable" and have eluded efforts at targeting with inhibitors until very recently.RAS proteins bind to guanosine diphosphate (GDP) and guanosine triphosphate (GTP) with high affinity.Hydrolysis of GTP to GDP switches RAS from its "active" to its "inactive" state.RAS proteins have an intrinsic GTPase activity, effectively leading them to be self-inactivating.Mutations in RAS result in a loss of this intrinsic GTPase activity, leaving the RAS protein in an activated GTPbound state and persistent stimulation of the downstream signalling cascade.Efforts at targeting RAS have been multimodal, including direct targeting of the mutated RAS protein and effectors in the downstream signalling cascade. Rationale for targeting KRAS in cancerThe rationale for targeting KRAS in cancer therapy stems from the knowledge of its distinct role in tumorigenesis.Preclinical studies have demonstrated that both primary and metastatic pancreatic cancers depend on sustained KRAS activity (4) and that transgenic mice that express KRAS V12G develop intestinal lesions including invasive adenocarcinoma (5).These findings, combined with the fact that mutations in KRAS are seen in approximately 30% of all cancers, make a strong argument for KRAS directed therapy.

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