Small molecular inhibitors for KRAS-mutant cancers

Abstract

Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered "undruggable", recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.

Keywords: RAS inhibitor; RAS mutation; combination strategy; different isoform; immunotherapy.

Figure 1

(A) An alignment of the carboxy terminus of the three RAS isoforms is shown. The RAS subtypes are highly conserved (~90%) with respect to the entire amino terminal GTPase domain (amino acids 1–166), which contains the GTP-GDP binding site and the interaction site of the effector protein; however, the carboxy terminal part differs and is called the hypervariable zone. (B) Percentages of KRAS mutations in codon 12 and NRAS mutations in codon 61 by tissue type for common cancers. (C) The canonical nature of RAS is characteristic of a small GTPase that usually circulates between the GTP-bound active state and GDP-bound inactive state, which is partly promoted by the GTP hydrolysis-stimulating GTPase activation protein (GAP). However, when the RAS protein is mutated, impaired GAP stimulation promotes the formation of a persistently GTP-bound RAS. (D) An overview of the general biochemical destruction of hydrolysis and guanine exchange after mutation of codon 12 or 61.

Figure 2

RAS mutation activates the protein, and the complex formed with GTP binds to the Ras-binding domain of the effector protein (RAF, PI3K, and RALGDS) to activate the MAPK and PI3K signaling pathways, respectively. The signals are transduced into the nucleus to regulate gene expression, thereby affecting cell proliferation and survival. Inhibition of SOS or SHP2 reduces the exchange rate between GDP and GTP and reduces the GTP-bound RAS population. Mutated RAS proteins accumulate in the GTP-bound state. Many inhibitors have been developed to directly inhibit RAS, including covalent allele-specific inhibitors that bind to KRAS-G12C.