sotorasib and Neoplasms

Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRAS

Topics: Acetonitriles; Antineoplastic Agents; Cell Transformation, Neoplastic; DNA, Neoplasm; Humans; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Oncogenic KRAS is one of the most common drivers of human cancer. Despite intense research, no effective therapy to directly inhibit oncogenic KRAS has yet been approved and KRAS mutant tumors remain associated with a poor prognosis. This short review discusses the current knowledge of the redox regulation of RAS and examines the newest findings on cysteine 118 (C118) as a potential novel target for KRAS inhibition.

Topics: Animals; Antineoplastic Agents; Cysteine; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; Mutation; Neoplasms; Nitrosation; Oxidation-Reduction; Piperazines; Protease Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Signal Transduction; Sulfinic Acids

Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRAS

Topics: Acetonitriles; Antineoplastic Agents; Gene Expression Regulation; Humans; Mutant Proteins; Mutation; Neoplasms; Pacemaker, Artificial; Piperazines; Protein Conformation; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Signal Transduction; SOS1 Protein; Structure-Activity Relationship

RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRAS

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Piperazines; Pyridines; Pyrimidines; ras Proteins; Signal Transduction

RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.

Topics: Acetonitriles; Allosteric Regulation; Allosteric Site; Animals; Antineoplastic Agents; Catalytic Domain; Cell Membrane; Dimerization; Drug Design; GTP Phosphohydrolases; Humans; Metabolism; Mice; Molecular Conformation; Mutation; Neoplasm Transplantation; Neoplasms; Piperazines; Protein Conformation; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; ras Proteins; Signal Transduction

No therapies for targeting. We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the. A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.. Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Fungal Proteins; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines

For decades, KRAS G12C was considered an undruggable target. However, in recent times, a covalent inhibitor known as sotorasib was discovered and approved for the treatment of patients with KRAS G12C-driven cancers. Ever since the discovery of this drug, several preclinical efforts have focused on identifying novel therapeutic candidates that could act as covalent binders of KRAS G12C. Despite these intensive efforts, only a few KRAS G12C inhibitors have entered clinical trials. Hence, this highlights the need to develop effective drug candidates that could be used in the treatment of KRAS G12C-driven cancers. Herein, we embarked on a virtual screening campaign that involves the identification of pharmacophores of sotorasib that could act as covalent arsenals against the KRAS G12C target. To our knowledge, this is the first computational study that involves the compilation of sotorasib pharmacophores from an online chemical database against KRAS G12C. After this library of chemical entities was compiled, we conducted a covalent docking-based virtual screening that revealed three promising drug candidates (CID_146235944, CID_160070181, and CID_140956845) binding covalently to the crucial nucleophilic side chain of Cys12 and interact with the residues that form the cryptic allosteric pocket of KRAS G12C in its inactive GDP-bound conformation. Subsequently, ADMET profiling portrayed the covalent inhibitors as lead-like candidates, while 100 ns molecular dynamics was used to substantiate their stability. Although our overall computational study has shown the promising potential of the lead-like candidates in impeding oncogenic RAS signaling, more experimental efforts are needed to validate and establish their preclinical relevance. Implication of KRAS G12C in cancer and computational approach towards impeding the KRAS G12C RAS signaling.

Topics: Humans; Lung Neoplasms; Molecular Dynamics Simulation; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras)

KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRAS

Topics: Carcinogenesis; Humans; Mutation; Neoplasms; Oligopeptides; Oncogenes; Proto-Oncogene Proteins p21(ras)

Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS

Topics: Cysteine; Genes, ras; Humans; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras)

KRAS is one of the most heavily mutated oncogenes in cancer and targeting mutant KRAS with drugs has proven difficult. However, recent FDA approval of the KRAS G12C selective inhibitor sotorasib (AMG-510), has breathed new life into the drive to develop mutant KRAS inhibitors. In an effort to study RAS inhibitors in cells and identify new compounds that inhibit Ras signaling, western blotting and ELISA assays are commonly used. These traditional immunoassays are tedious, require multiple washing steps, and are not easily adaptable to a high throughput screening (HTS) format. To overcome these limitations, we applied Lumit immunoassay technology to analyze RAS signaling pathway activation and inhibition through the detection of phosphorylated ERK. The assay we developed was used to rank order potencies of allele specific inhibitors within cell lines harboring various activating KRAS mutations. An inhibition profile was obtained indicating various potencies and selectivity of the inhibitors, including MRTX-1133, which was shown to be highly potent against KRAS G12D signaling. MRTX-1133 had approximately 40 and 400 times less inhibitory potency against G12C and G12V mutant KRAS, respectively, while no inhibition of WT KRAS was observed. The potency of PROTAC compound LC-2 targeting selective degradation of KRAS G12C was also tested using the Lumit pERK immunoassay, and a maximal decrease in RAS signaling was achieved. Lumit immunoassays provide a rapid, homogeneous platform for detecting signaling pathway activation and inhibition. Our results demonstrate that this bioluminescent technology can streamline the analysis of signaling pathways of interest, such as RAS-dependent pathways, and be used to identify much needed inhibitors. The results further imply that similar assay designs could be applied to other signaling pathway nodes.

Topics: Antineoplastic Agents; Extracellular Signal-Regulated MAP Kinases; Humans; Immune Checkpoint Inhibitors; Immunoassay; Neoplasms; Oncogenes; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Maximum Tolerated Dose; Neoplasms; Piperazines; Pyridines; Pyrimidines; United States; United States Food and Drug Administration

Topics: Acetonitriles; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line; Cohort Studies; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; GTP Phosphohydrolases; Humans; MAP Kinase Signaling System; Membrane Proteins; Mice; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Xenograft Model Antitumor Assays

Topics: Acetonitriles; Antineoplastic Agents; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.

Topics: Animals; Antineoplastic Agents; Drug Design; Drug Evaluation, Preclinical; Genes, ras; Humans; Mice; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Signal Transduction; Translational Research, Biomedical; Treatment Outcome