Importance of RAS/RAF/MEK/ERK pathway in human cancers

The RAS/RAF/MEK/ERK pathway is activated in many human tumors and plays key roles in driving proliferation, suppressing apoptosis, and mediating other aspects of the transformed phenotype. Multiple mechanisms have been described that directly activate the RAS/RAF/MEK/ERK pathway, including abnormal activation of upstream growth factor receptors or gain-of-function mutations in the KRAS, NRAS or BRAF genes.

The inhibition of the RAS/RAF/MEK/ERK pathway has long been an attractive therapeutic target for cancer treatment, particularly for the treatment of KRAS-mutant, NRAS-mutant, and BRAF-mutant cancers:

RAS-NRAS-BRAF-cancers

RAS proteins are small GTPases that act as molecular switches controlling signaling pathways regulating cell proliferation and cell survival. When bound to guanosine triphosphate (GTP), RAS becomes active and signals via networks that include RAF/MEK/ERK.

RAS has three known isoforms:

Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS). The three RAS genes are among the most frequently mutated genes in cancer, with KRAS being the most commonly mutated oncogene. Approximately 30% of all human cancers are driven by mutations of the RAS family of genes and are highly aggressive and recurrent. Mutations in KRAS account for about ~85% for all RAS mutations in human tumors, NRAS is about ~11–15%, and HRAS is about ~1%.

Direct inhibition of oncogenic RAS has been challenging due to its high affinity for GTP/GDP and the lack of a clear binding pocket. More recently, compounds were identified that covalently bind to KRAS G12C at the cysteine 12 residue, lock the protein in its inactive GDP-bound conformation, inhibit KRAS-dependent signaling, and elicit antitumor responses in tumor models and phase 1 clinical studies. However, while KRASG12C inhibitors are promising, these agents would be effective in only a small percentage of patients with KRAS-mutant cancers since the G12C mutation only accounts for about 15% for all KRAS mutations in human tumors (TCGA PanCancer Atlas).

Over the past several years, research efforts have focused on alternatives to the elusive challenge of directly targeting RAS. Several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. Inhibitors of RAF and MEK kinases have shown clinical efficacy.