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Ras plays a pivotal function in cell proliferation and is an important protein in signal transduction pathways. Mutations in genes encoding the Ras protein drive the signaling cascades essential for malignant transformation, tumour angiogenesis, and metastasis and are responsible for above 30% of all human cancers. There is evidence that N-Ras, K-Ras, and H-Ras play significant roles in human cancer. The mutated K-Ras protein is typically observed in malignant growths. Mutant K-Ras is the most common in lung, colon, and pancreatic cancers. The purpose of this research was to create peptides that inhibit K-Ras G12V. The crystal structure of the mutant K-Ras G12V-H-REV107 complex was obtained from a protein data bank. Further, we used a residue scan approach to create unique peptides from the reference peptide (H-REV107). AMBER molecular dynamics simulations were used to test the stability of the top four proposed peptides (based on binding free energies). Our findings showed that the top four selected peptides had stronger interactions with K-Ras than the reference peptide and have the ability to block the activation function of K-Ras. Our extensive analyses of binding affinities showed that our designed peptide possesses the potential to inhibit K-Ras and to reduce the progression of cancer.

[This corrects the article DOI: 10.1371/journal.pone.0176578.].

A study involving 38 patients who initially had a response to adagrasib or who had a long period of stable disease in response to the drug but then had progression yielded diverse mechanisms of acquired resistance in 45% of them. Unlike resistance to the tyrosine kinase inhibitors, the cancer cell uses many mechanisms to overcome the inhibition of KRAS.

Adagrasib produced responses in 43% of previously treated patients with non–small-cell lung cancer containing a KRAS G12C mutation, with median overall survival of 12.6 months. Regressions of stable brain metastases were noted in one third of evaluable patients. Gastrointestinal toxic effects dominated the adverse events, but fewer than 7% of patients stopped therapy.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered ‘undruggable’ owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients 1 – 7 . Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers. A non-covalent inhibitor that binds preferentially to the inactive state of KRAS while sparing NRAS and HRAS is reported, indicating that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells.

Sotorasib is a selective irreversible inhibitor of the G12C-activated KRAS oncogene, present in approximately 13% of non–small-cell lung cancers. In a single-group, phase 2 trial involving 126 patients with previously treated KRAS p.G12C–mutated NSCLC, 37% had a response (median duration, 11 months). One fifth of patients had grade 3 toxic effects, mainly liver-enzyme abnormalities and diarrhea.

RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61 1 . Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer 2 , 3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS -mutated cancers 4 , 5 , and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations ( KRAS G12X ). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS G12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS -mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985). RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

Recent progress in targeting KRAS G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS G12D with K D and IC 50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS G12D as compared to KRAS WT . MRTX1133 also demonstrated potent inhibition of activated KRAS G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines, with median IC 50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS G12D -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival. A potent and selective inhibitor of KRAS G12D , the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.