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Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer.

ABSTRACT: HRas-GTP has a transient intermediate state with a "non-signaling open conformation" in GTP hydrolysis and nucleotide exchange. Due to the same hydrolysis process and the structural homology, it can be speculated that the active KRas adopts the same characteristics with the "open conformation." This implies that agents locking this "open conformation" may theoretically block KRas-dependent signaling. Applying our specificity-affinity drug screening approach, NSC290956 was chosen by high affinity and specificity interaction with the "open conformation" structure HRasG60A-GppNp. In mutant KRas-driven non-small-cell lung cancer (NSCLC) model system, NSC290956 effectively suppresses the KRas-GTP state and gives pharmacological KRas inhibition with concomitant blockages of both the MAPK-ERK and AKT-mTOR pathways. The dual inhibitory effects lead to the metabolic phenotype switching from glycolysis to mitochondrial metabolism, which promotes the cancer cell death. In the xenograft model, NSC290956 significantly reduces H358 tumor growth in nude mice by mechanisms similar to those observed in the cells. Our work indicates that NSC290956 can be a promising agent for the mutant KRas-driven NSCLC therapy.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8766838 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer.

Zhang Jiaxin J Liu Zuojia Z Zhao Wenjing W Yin Xunzhe X Zheng Xiliang X Liu Chuanbo C Wang Jin J Wang Erkang E

Frontiers in pharmacology 20220105

HRas-GTP has a transient intermediate state with a "non-signaling open conformation" in GTP hydrolysis and nucleotide exchange. Due to the same hydrolysis process and the structural homology, it can be speculated that the active KRas adopts the same characteristics with the "open conformation." This implies that agents locking this "open conformation" may theoretically block KRas-dependent signaling. Applying our specificity-affinity drug screening approach, NSC290956 was chosen by high affinity ...[more]

PMID: 35069209

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Project description:ObjectiveKirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non-small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS-mutant NSCLC. This study aimed to assess real-world data of Chinese patients with KRAS-mutant NSCLC undergoing chemotherapy and/or immunotherapy.MethodsKRAS mutational status was analyzed using next-generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II).ResultsIn Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first-line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression-free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48-0.88, p = 0.033 and HR = 0.69, 95% CI 0.47-1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16-13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35-0.99, p = 0.049).ConclusionKRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS-mutant NSCLC could benefit from pemetrexed-based chemotherapy and ICIs.

Dataset Information

Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer.

Publications

Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer.

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