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Genetic variants in LKB1/AMPK/mTOR pathway are associated with clinical outcomes of chemotherapy in non-small cell lung cancer.

ABSTRACT: This study was conducted to investigate the relationship between genetic variants in LKB1/AMPK/mTOR pathway and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. A total of 379 patients with NSCLC who underwent first-line paclitaxel-cisplatin chemotherapy was enrolled. The associations between 19 single nucleotide variants (SNVs) in the LKB1/AMPK/mTOR pathway and the chemotherapy response and overall survival (OS) were analyzed. Among the SNVs analyzed, AKT1 rs2494750G>C and TSC1 rs2809244C>A were associated with clinical outcomes after chemotherapy in multivariate analyses. The AKT1 rs2494750G>C was significantly associated with a better response to chemotherapy (adjusted odds ratio [aOR]: 1.92, 95% confidence interval [CI]: 1.02-3.62, p = 0.04). The TSC1 rs2809244C>A were significantly associated with better OS (adjusted hazard ratio [aHR]: 0.79, 95% CI: 0.62-0.99, p = 0.04). When stratified by tumor histology, AKT1 rs2494750G>C exhibited a significant association with the chemotherapy response only in adenocarcinoma and TSC1 rs2809244C>A was also significantly associated with OS only in adenocarcinoma. This result suggests that the AKT1 rs2494750G>C and TSC1 rs2809244 C>A may be useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.

SUBMITTER: Choi SH

PROVIDER: S-EPMC9715851 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Genetic variants in LKB1/AMPK/mTOR pathway are associated with clinical outcomes of chemotherapy in non-small cell lung cancer.

Choi Sun Ha SH Do Sook Kyung SK Lee Shin Yup SY Choi Jin Eun JE Kang Hyo-Gyoung HG Hong Mi Jeong MJ Lee Jang Hyuck JH Lee Won Kee WK Jeong Ji Yun JY Shin Kyung Min KM Do Young Woo YW Lee Eung Bae EB Park Ji Eun JE Lee Yong Hoon YH Seo Hyewon H Yoo Seung Soo SS Lee Jaehee J Cha Seung Ick SI Kim Chang Ho CH Park Jae Yong JY

Thoracic cancer 20221014 23

This study was conducted to investigate the relationship between genetic variants in LKB1/AMPK/mTOR pathway and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. A total of 379 patients with NSCLC who underwent first-line paclitaxel-cisplatin chemotherapy was enrolled. The associations between 19 single nucleotide variants (SNVs) in the LKB1/AMPK/mTOR pathway and the chemotherapy response and overall survival (OS) were analyzed. Among the SNVs anal ...[more]

PMID: 36239337

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Project description:IntroductionLiver kinase B1 (LKB1), also called serine/threonine kinase 11 (STK11), is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Approximately 30% to 35% of patients with NSCLC possess inactivated liver kinase B1 gene (LKB1), and these patients respond poorly to anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy. Therefore, novel therapies targeting NSCLC with LKB1 loss are needed.MethodsWe used a new in silico signaling analysis method to identify the potential therapeutic targets and reposition drugs by integrating gene expression data with the Kyoto Encyclopedia of Genes and Genomes signaling pathways. LKB1 wild-type and LKB1-deficient NSCLC cell lines, including knockout clones generated by clustered regularly interspaced short pallindromic repeats-Cas9, were treated with inhibitors of mechanistic target of rapamycin kinase (mTOR) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and a dual inhibitor.ResultsIn silico experiments showed that inhibition of both mTOR and PI3K can be synergistically effective in LKB1-deficient NSCLC. In vitro and in vivo experiments showed the synergistic effect of mTOR inhibition and PI3K inhibition in LKB1-mutant NSCLC cell lines. The sensitivity to dual inhibition of mTOR and PI3K is higher in LKB1-mutant cell lines than in wild-type cell lines. A higher compensatory increase in Akt phosphorylation after rapamycin treatment of LKB1-deficient cells than after rapamycin treatment of LKB1 wild-type cells is responsible for the synergistic effect of mTOR and PI3K inhibition. Dual inhibition of mTOR and PI3K resulted in a greater decrease in protein expression of cell cycle-regulating proteins in LKB1 knockout cells than in LKB1 wild-type cells.ConclusionDual molecular targeted therapy for mTOR and PI3K may be a promising therapeutic strategy in the specific population of patients with lung cancer with LKB1 loss.

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Dataset Information

Genetic variants in LKB1/AMPK/mTOR pathway are associated with clinical outcomes of chemotherapy in non-small cell lung cancer.

Publications

Genetic variants in LKB1/AMPK/mTOR pathway are associated with clinical outcomes of chemotherapy in non-small cell lung cancer.

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