Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRAS^G12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Keywords: Colorectal cancer; Combination therapy; G12C; KRAS; Prognosis; Targeted therapy.

Fig. 1

KRAS signaling pathway and relevant inhibitors of each node. After the activation of receptor tyrosine kinase, GRB2 combines with the guanine nucleotide exchange factor SOS and then interacts with KRAS protein that is attached to the cell membrane, thereby promoting KRAS activation. Intrinsic KRAS GTP-GDP cycling is regulated by GEFs and GAPs. Once KRAS is mutated, this cycle is disrupted, allowing mutant KRAS protein to accumulate in an active state and thereby persistently activating downstream MAPK and PI3K signaling cascade, resulting in cell proliferation and survival. Various KRAS inhibitors listed in the box were developed to target each node of the KRAS signaling pathway and then evaluated in preclinical or clinical studies. Created with BioRender.com

Fig. 2

Frequency and distribution of KRAS mutations in CRC and the biochemical features of mutant KRAS proteins. a Percentage of KRAS mutation in CRC and the diversity of KRAS alleles. Data acquired from The Cancer Genome Atlas (pan-Cancer) from cBioPortal. b Overview of generalized biochemical change of hydrolysis and guanine exchange following mutations in codons 12 (orange), 13 (purple) or, 61 (blue). The dashed line indicates hydrolysis and the solid line indicates guanine exchange, with the thicker line indicating faster rates and vice versa for slower rates. Created with BioRender.com. WT, wild type; MUT, mutant type

Fig. 3

Chemical structures of KRAS^G12C covalent inhibitors with their initial publication date. AMG 510 has received accelerated approval from the U.S. FDA for the treatment of patients with NSCLC in May 2021. MRTX849 has been granted Breakthrough Therapy Designation by FDA in June 2021