Rapamycin and trametinib: a rational combination for treatment of NSCLC

Sun, Chen; Li, Yizhuo; Cao, Di; Zhou, Yufeng; Zhang, Mei‐Yin; Wang, Huiyun

doi:10.7150/ijbs.62752

Cited by 11 publications

(11 citation statements)

References 44 publications

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“…Chen et al ( 47 ) showed that rapamycin greatly enhanced dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human lung adenocarcinoma A549 cells, without affecting apoptosis. Sun et al ( 48 ) demonstrated that a combination of rapamycin and trametinib could more effectively inhibit NSCLC cell viability and proliferation. The reason for this discrepancy between the results of the present study and those of the aforementioned two studies may be that rapamycin used alone to treat cells mainly activates the autophagy pathway, while synergistic action with other anticancer drugs affects other pathways, thus leading to different results.…”

Section: Discussionmentioning

confidence: 99%

PEDF inhibits non‑small cell lung cancer proliferation by suppressing autophagy through downregulation of AMPK‑ULK1 signaling

Miao

Hui

et al. 2022

Oncol Rep

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Current investigations suggest that pigment epithelial-derived factor (PEDF) can mediate the progression of non-small cell lung cancer (NSCLC) by regulating autophagy. However, the underlying mechanisms associated with autophagy remain poorly elucidated. The aim of the present study was to investigate the association between the PEDF/adenosine 5'-monophosphate-activated protein kinase (AMPK)/Unc-51 like autophagy-activated kinase 1 (ULK1) pathway and autophagy in NSCLC. Intracellular autophagy was evaluated using indicators such as the expression and activation of microtubule-associated protein light chain 3-I (LC3-I), LC3-II and p62, as well as the distribution and number of autophagosomes observed by confocal microscopy. In addition, the activity and proliferative capacity of NSCLC cells under PEDF overexpression was also examined using Cell Counting Kit-8 and lactate dehydrogenase (LDH) assays, and western blotting (WB) of related proteins. The results revealed that PEDF significantly inhibited NSCLC cell proliferation and viability, and increased LDH release and intercellular adhesion. Furthermore, PEDF suppressed the expression and activation of LC-3 and reduced the number and distribution of autophagosomes. The PEDF-induced inhibition of autophagy exhibited a direct association with the suppressed proliferation capacity and cell viability of NSCLC cells. The results of WB showed that NSCLC cells regulated autophagy through the AMPK/ULK1 signaling pathway. PEDF downregulated the AMPK/ULK1 signaling pathway, and AMPK or ULK1 overexpression markedly reduced the inhibitory effect of PEDF on autophagy. In conclusion, PEDF overexpression significantly inhibited the proliferative capacity and cell viability of NSCLC cells, as PEDF exerted an inhibitory function by regulating autophagy in NSCLC cells. Finally, it was demonstrated that autophagy may be suppressed by inhibiting the AMPK/ULK1 signaling pathway, thereby revealing a mechanism of lung cancer progression.

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Section: Discussionmentioning

confidence: 99%

PEDF inhibits non‑small cell lung cancer proliferation by suppressing autophagy through downregulation of AMPK‑ULK1 signaling

Miao

Hui

et al. 2022

Oncol Rep

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“…Drugs were administrated daily through intraperitoneal injection for 18 days. Treatment conditions were chosen as previously reported 34,37–39 . Tumour volume was calculated using the formula: V = ( L × W 2 )/2.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment conditions were chosen as previously reported. 34,[37][38][39] Tumour volume was calculated using the formula:…”

Section: Methylated Rna Immunoprecipitationmentioning

confidence: 99%

Methyltransferase‐like 3 promotes the progression of lung cancer via activating PI3K/AKT/mTOR pathway

Cheng

Peng

Luo

2022

Clin Exp Pharma Physio

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Methyltransferase-like 3 (METTL3) catalyses N6-methyladenosine (m 6 A) modification on messenger RNA (mRNA) and participates in a wide range of biological functions via epigenetically regulating gene expression. Recent studies suggested that dysregulation of METTL3 is associated with multiple human cancers; however, the role of METTL3 in lung cancer remains unclear. In the present study, through transcriptome analysis of lung cancer patients, we found that METTL3 is overexpressed in lung cancer patients and is associated with poor patient survival. More importantly, combining both in vitro and in vivo models, we revealed that in lung cancer cells, METTL3 overexpression activates PI3K/AKT/mTOR pathway and mTORmediated protein synthesis. Mechanistically, METTL3 promotes PI3K expression by introducing m 6 A modification in PI3K 3 0 untranslated region (3 0 UTR). Elevated PI3K level then activates downstream AKT and mTOR signalling pathway and results in rapid cancer cell proliferation and metastasis. Taken together, our study reveals that METTL3-mediated m 6 A methylation promotes lung cancer progression via activating PI3K/AKT/mTOR pathway.

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“…All cell lines were cultured in RPMI-1640 medium (Gibco, United States), supplemented with 10% FBS (Gibco, United States), and maintained at 37°C in a standard incubator (5% CO 2 ). In addition, abemaciclib-resistant A549 cells were developed through serial passaging with dose-escalation of abemaciclib for 3 months by continuous drug exposure ( Pesch et al, 2020 ; Sun et al, 2021b ).…”

Section: Methodsmentioning

confidence: 99%

“…Cell viability was measured as described previously ( Sun et al, 2021b ). Briefly, cells were seeded into 96-well plates at 4,000 cells per well, and continuously cultured for 24 h. Then, cells were treated with abemaciclib or gilteritinib alone, or in combination.…”

Section: Methodsmentioning

confidence: 99%

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

et al. 2022

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Abemaciclib is a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor approved for the treatment of metastatic breast cancer. Preclinical studies suggest that abemaciclib has the potential for lung cancer treatment. However, several clinical trials demonstrate that monotherapy with abemaciclib has no obvious superiority than erlotinib to treat lung cancer patients, limiting its therapeutic options for lung cancer treatment. Here, we show that the US Food and Drug Administration (FDA)-approved drug, gilteritinib, enhances the cytotoxicity of abemaciclib through inducing apoptosis and senescence in lung cancer cells. Interestingly, abemaciclib in combination with gilteritinib leads to excessive accumulation of vacuoles in lung cancer cells. Mechanistically, combined abemaciclib and gilteritinib induces complete inactivation of AKT and retinoblastoma (Rb) pathways in lung cancer cells. In addition, RNA-sequencing data demonstrate that combination of abemaciclib and gilteritinib treatment induces G2 phase cell-cycle arrest, inhibits DNA replication, and leads to reduction in homologous recombination associated gene expressions. Of note, abemaciclib-resistant lung cancer cells are more sensitive to gilteritinib treatment. In a mouse xenograft model, combined abemaciclib and gilteritinib is more effective than either drug alone in suppressing tumor growth and appears to be well tolerated. Together, our findings support the combination of abemaciclib with gilteritinib as an effective strategy for the treatment of lung cancer, suggesting further evaluation of their efficacy is needed in a clinical trial.

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Rapamycin and trametinib: a rational combination for treatment of NSCLC

Cited by 11 publications

References 44 publications

PEDF inhibits non‑small cell lung cancer proliferation by suppressing autophagy through downregulation of AMPK‑ULK1 signaling

PEDF inhibits non‑small cell lung cancer proliferation by suppressing autophagy through downregulation of AMPK‑ULK1 signaling

Methyltransferase‐like 3 promotes the progression of lung cancer via activating PI3K/AKT/mTOR pathway

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

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