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Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS^G12C.

ABSTRACT: Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (e.g., KRAS ^G12V/D ) that are also vital for the occurrence, KRAS ^G12C gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. However, there are only a few therapeutic drugs targeting KRAS^G12C mutations currently. Here, we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^G12C binding affinity and the same anti-tumor effect based on the α-helical peptide mimic SAH-SOS1_A. The stapled peptide 3 effectively induced G2/M arrest and apoptosis, inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities, as well as good plasma stability and human liver microsomal metabolic stability. Overall, peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_A but with improved stability and affinity, superior to SAH-SOS1_A. Our work offers a structural optimization approach of KRAS^G12C peptide inhibitors for cancer therapy.

SUBMITTER: Li C

PROVIDER: S-EPMC8463269 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASG12C.

Li Cuicui C Zhao Ni N An Luyan L Dai Zhen Z Chen Xiaoyi X Yang Fan F You Qidong Q Di Bin B Hu Chi C Xu Lili L

Acta pharmaceutica Sinica. B 20210625 9

Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (e.g., KRAS G12V/D ) that are also vital for the occurrence, KRAS G12C gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. Howeve ...[more]

PMID: 34589388

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Project description:BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA 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.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Dataset Information

Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS^G12C.

Publications

Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS<sup>G12C</sup>.

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