Current location: Home > NEWS > Industry news
NEWS
PRODUCTS
Inhibitors of KRAS gene and drug resistance mechanism
News source: Release time:[2022-04-11]
Preface
KRAS is a common cancer mutation gene, especially in pancreatic cancer, lung cancer and colorectal cancer. Although it is very important, researchers have failed to develop a drug that can inhibit the function of KRAS protein for many years, which has won the title of "no patent medicine" for KRAS. Recently, efforts to develop mutation specific inhibitors have been relatively successful. Several KRAS G12C inhibitors have shown clinical benefits and have been approved or close to approval, including Sotorasib and Adagrasib. However, some studies also show that the role of these drugs in vivo will be limited by drug resistance, and combined treatment may be a potential method to overcome drug resistance.
01 Gene KRAS
RAS is one of the most common human oncogenes, and functional acquired mutations have been found in 27% of cancers. Three human RAS genes: Neuroblastoma Ras virus (v-ras) oncogene homologue (NRAS), Harvey rat sarcoma virus oncogene homologue (HRAS) and Kirsten rat sarcoma virus oncogene homologue (KRAS) encode four Ras GTPases (GTPases): NRAS, HRAS, Krasa and krasb. The latter two are the result of alternative splicing.KARs gene encodes a small GTPase with 188 amino acids and a molecular weight of 21.6 KD.
Ras protein circulates between active GTP binding state and inactive GDP binding state. This process is strictly regulated by a variety of multi domain protein families: guanine nucleotide exchange factor (GEF) and GTPase activating protein (GAP).GEF stimulates GDP dissociation and subsequent GTP binding, activating Ras protein; GAP accelerates the hydrolysis of bound GTP and converts Ras into inactive state. Ras protein plays an important role in cell proliferation, differentiation and survival by associating with a variety of downstream pathways, the most typical of which are MAPK and PI3K / AKT pathways.
▲ regulation of Ras protein
KRAS is the most common RAS mutation gene in most cancers, accounting for 85% of carcinogenic ras mutations.KRAS mutations are most common in epithelial cancer, such as pancreatic cancer, colorectal cancer and lung adenocarcinoma. According to the data of TCGA PanCancer Atlas Studies, the variation of KRAS was found in about 64% of pancreatic cancer and 37% of colorectal cancer. A multicenter cohort study of 40804 cases led by Guangdong Institute of lung cancer found that the mutation frequency of KRAS in NSCLC patients in China was 9.8%.
▲ mutation frequency of KRAS gene in Chinese patients with NSCLC
Carcinogenic mutations in Ras family are most common in codons 12, 13 and 61. The vast majority (83%) of cancer-related mutations in KRAS gene occur in codon 12.Missense mutations in codons 12 and 13 are thought to limit the interaction between GAP protein and GTPase site of Ras protein, so as to prevent the hydrolysis of GTP to inactive state of Ras protein. The proportion of KRAS gene G12C mutation in NSCLC population in China accounts for about 30% of all KRAS mutations. The vast majority of KRAS mutations are associated with poor prognosis. Although the frequency of KRAS mutation in pancreatic cancer is high, G12C is only a secondary subtype (~1%).
02 Inhibitor KRAS
KRAS has proved to be a difficult drug target. The picomolar affinity of Ras protein binding to GTP prevents efforts to develop competitive inhibitors of GTP.In addition, attempts to directly target KRAS are hampered by its structure: KRAS presents a smooth surface without deep drainage bags that allow tight binding. Therefore, past efforts have shifted their focus to other targets, such as farnesyltransferase inhibitors (FTI) and inhibitors downstream of Ras. But so far, these studies have failed to show significant clinical benefits.
ARS-1620 is the first G12C specific inhibitor that can show efficacy in vivo. Since then, there are several other related compounds with stronger biological activity, among which Adagrasib (MRTX849) and Sotorasib (AMG 510) first entered the clinic.The action principle of G12C inhibitor is: when KRAS is in its inactive and GDP binding state, the inhibitor covalently binds to the mutated cysteine residue and occupies a pocket in switch II region (siip), so as to keep KRAS in the inactive GDP binding state.
▲ action mechanism of G12C inhibitor
Sotorasib(AMG 510)
On May 29, 2021, the FDA approved Amgen's targeted anticancer drug Lumakras (Sotorasib, AMG 510) for the treatment of patients who have received at least one prior systemic therapy and have been confirmed by an FDA-approved test. For adult patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC,Its clinical study CodeBreak (NCT03600883) achieved an objective response rate (ORR) of 36% in the late-line treatment, with a median PFS of 6.8 months and a median OS of 12.5 months.
▲ codebreak research results
CodeBreak also conducted an exploratory analysis to evaluate the potential association between sotorasib treatment response and baseline tumor PD-L1 expression level, TMB, STK11, Keap1 and TP53.Efficacy was also observed in subgroups of STK11, Keap1 or TP53 co mutations that were generally considered insensitive to G12C inhibitors.