The path to the clinic: a comprehensive review on direct KRASG12C inhibitors

Abstract

The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRAS^G12C mutation. Adagrasib (MRTX849) and other direct KRAS^G12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRAS^G12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS^G12C inhibitors and summarize the ongoing clinical trials of all direct KRAS^G12C inhibitors.

Keywords: Adagrasib; Cancer; Clinical trial; Direct RAS inhibitor; Drug development; Epidemiology; Immunotherapy; KRASG12C; Sotorasib.

Fig. 1

The G domain corresponds to the initial 166–168 residues. Bordering the nucleotide-binding pocket are four main regions: the phosphate-binding loop (P-loop, residues 10–17), switch I (residues 30–38), switch II (residues 60–76) and the base-binding loops (residues 116–120 and 145–147). The two switch regions regulate all known nucleotide-dependent interactions between RAS and its binding partners. The remaining residues in the carboxy-terminal constitutes the HVR, including the CAAX motif, a membrane anchor sequence. Abbreviations: HVR, hypervariable region; CAAX, C: cysteine amino acid, A: aliphatic amino acid, X: amino acid dictating whether farnesylated or geranylated

Fig. 2

RAS proteins play a pivotal role in the regulation of cell proliferation, differentiation, and survival through various signal transduction cascades, including the canonical RAF–MEK–ERK/MAPK, PI3K–AKT–mTOR, and RALGDS–RAL pathways. Once the ligand binds to the extracellular domain of the RTK, the signal is transmitted through the transmembrane domain resulting in RTK dimerization and subsequent RAS activation. RAS signaling is further regulated by a balance between activation by GEF’s (e.g., SOS and RASGRP) and inactivation by GAP’s (e.g., NF and p120GAP). Abbreviations: RTK, receptor tyrosine kinase; GEF’s, guanine nucleotide exchange factors; GAP’s, GTPase-activating proteins; SOS, son of sevenless homologue; RASGRP, RAS guanyl nucelotide-releasing protein; NF, neurofibromin

Fig. 3

A The pie chart depicts the percentage of each RAS isoform contributing to all RAS mutations. Gain-of-function missense mutations in KRAS account for the majority of RAS gene mutations (75%), followed by NRAS mutations (17%) and HRAS mutations (7%). The remaining 1% represents RAS mutations that are other than gain-of-function missense mutations. Among KRAS mutations, the G12 codon (81%) is the most frequently mutated, followed by G13 (14%) and Q61 (2%). B The bar graph portrays the proportion of RAS mutations that are KRAS mutations found in a given cancer type. KRAS mutations are the most common RAS mutations in pancreatic cancer (~ 88%), followed by colon adenocarcinoma (50%), rectal adenocarcinoma (50%), lung adenocarcinoma (32%), small intestine adenocarcinoma (26%), cholangiocarcinoma (23%), plasma cell myeloma (18%), gallbladder carcinoma (16%), and anaplastic thyroid carcinoma (8.6%)

Fig. 4

This figure illustrates the chemical structures of the first direct KRAS^G12C inhibitors in the preclinical and clinical years. Compound 12 was the initial lead compound developed by the Shokat lab; it was subsequently optimized to ARS-853, the first direct small molecular inhibitor shown to selectively inhibit KRAS^G12C in cells with potency in the range of a drug candidate. Introduction of a quinazoline core and a fluorophenol hydrophobic binding moiety resulted in ARS-1620, the first drug candidate to demonstrate in vivo potency. In May 2021, AMG510 (sotorasib) became the first FDA-approved therapy to directly target KRAS-mutated tumors. In June 2021, MRTX849 (adagrasib) received breakthrough therapy designation by the FDA, driving MRTX849 nearer to entering the clinic as well

Fig. 5

The diagram illustrates the nine small molecular inhibitors in registered clinical trials that directly target the KRAS^G12C mutant by binding to the switch II pocket (S-IIP). These inhibitors preferentially bind and stabilize RAS in the GDP-bound state, ultimately resulting in decreased signal transduction, especially by the RAF-MEK-ERK/MAP pathway, and thus preventing tumor progression