LKB1 gene inactivation does not sensitize non-small cell lung cancer cells to mTOR inhibitors in vitro

Xiao, Ping; Sun, Linlin; Wang, Jing; Han, Ruili; Ma, Qing; Zhong, Diansheng

doi:10.1038/aps.2015.19

Cited by 4 publications

(2 citation statements)

References 22 publications

(23 reference statements)

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“…4 The PI3K-Akt-mTOR signaling pathway has been investigated as a therapeutic target for LKB1-mutant neoplasms, but those studies have yielded controversial results. [7][8][9][10] In this study, we used a new signaling analysis method to identify the potential therapeutic targets and reposition drugs by integrating gene expression data with KEGG signaling pathway data and showed that inhibition of both mTOR and PI3K can be synergistically effective in LKB1-mutant NSCLC. We then demonstrated the synergistic effect of mTOR inhibition and PI3K inhibition in LKB1-deficient NSCLC cell lines in vitro and in vivo and showed that dual inhibition of mTOR and PI3K can be a promising therapeutic strategy in LKB1deficient tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Everolimus combined with a PI3K inhibitor, LY294002, enhanced the sensitivity in both LKB1 wild-type H1792 cells and LKB1-mutant A549 cells. 10 The goal of this study was to investigate whether mTOR/PI3K pathway inhibition can be used as a potential therapeutic strategy against LKB1-deficient NSCLC. We started with a new signaling pathway analysis method to identify the potential therapeutic targets and reposition existing drugs by integrating gene expression data with the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer

Shukuya

Yamada

Koenig

et al. 2019

Journal of Thoracic Oncology

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Introduction: Liver 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 antiprogrammed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy. Therefore, novel therapies targeting NSCLC with LKB1 loss are needed. Methods: We 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 3kinase (PI3K) and a dual inhibitor. Results: In 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 LKB1mutant 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. Conclusion: Dual 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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer

Shukuya

Yamada

Koenig

et al. 2019

Journal of Thoracic Oncology

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Hepatoprotective dibenzocyclooctadiene lignans from the fruits of Kadsura coccinea

Wu,

Liu,

Ruan

et al. 2024

Fitoterapia

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Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma

Lin

Rizvi

et al. 2021

Cancer Research

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The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1-mutant lung tumors to platinum therapy, was validated using a large patient response data set. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies. Significance: An experimental and analytical framework to generate in vivo pharmacogenomic maps that relate tumor genotypes to therapeutic responses reveals a surprisingly complex map of genotype-specific resistance and sensitivity.

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LKB1 gene inactivation does not sensitize non-small cell lung cancer cells to mTOR inhibitors in vitro

Cited by 4 publications

References 22 publications

The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer

The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer

Hepatoprotective dibenzocyclooctadiene lignans from the fruits of Kadsura coccinea

Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma

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