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Rapamycin and trametinib: a rational combination for treatment of NSCLC
Chao-Yue Sun1, Yi-Zhuo Li2, Di Cao2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China 510060.
Abstract:
Mammalian target of rapamycin (mTOR) is one of the most commonly activated pathways in human cancers, including lung cancer. Targeting mTOR with molecule inhibitors is considered as a useful therapeutic strategy. However, the results obtained from the clinical trials with the inhibitors so far have not met the original expectations, largely because of the drug resistance. Thus, combined or multiple drug therapy can bring about more favorable clinical outcomes. Here, we found that activation of ERK pathway was responsible for rapamycin drug resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible to rapamycin. Combining rapamycin with trametinib led to a potent synergistic antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in combination with trametinib resulted in a greater decrease of phosphorylation of AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC.
Insights
Combining rapamycin with trametinib, an ERK inhibitor, overcomes drug resistance in non-small-cell lung cancer (NSCLC). This synergistic therapy shows potent antitumor effects and minimal toxicity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers, including lung cancer.
- mTOR inhibitors show promise but face challenges due to acquired drug resistance.
- Drug resistance mechanisms, such as ERK pathway activation, limit the efficacy of single-agent therapies.
Purpose of the Study:
- To investigate the role of ERK pathway activation in rapamycin resistance in non-small-cell lung cancer (NSCLC).
- To evaluate the efficacy of combining mTOR inhibitors with ERK inhibitors for NSCLC treatment.
- To elucidate the molecular mechanisms underlying the synergistic effects of combined therapy.
Main Methods:
- Utilized non-small-cell lung cancer (NSCLC) cell lines with acquired resistance to rapamycin.
- Assessed the sensitivity of resistant cells to ERK inhibitors (trametinib, MEK162).
- Evaluated the synergistic antitumor efficacy of combined rapamycin and trametinib in vitro and in a xenograft mouse model.
- Analyzed molecular changes, including protein phosphorylation (AKT, ERK, mTOR, 4EBP1).
Main Results:
- Activation of the ERK pathway was identified as a key mechanism of rapamycin resistance in NSCLC.
- Rapamycin-resistant NSCLC cells demonstrated increased sensitivity to trametinib, and vice versa.
- Combined administration of rapamycin and trametinib exhibited potent synergistic antitumor activity, inducing G1-phase cell cycle arrest and apoptosis.
- The combination therapy led to a significant decrease in the phosphorylation of AKT, ERK, mTOR, and 4EBP1.
- Co-administration in a xenograft mouse model suppressed tumor growth effectively with no significant drug toxicity.
Conclusions:
- Combined inhibition of mTOR and ERK pathways represents a rational and effective therapeutic strategy for NSCLC.
- This combination overcomes rapamycin resistance mediated by ERK pathway activation.
- The synergistic effects are mechanistically linked to the simultaneous suppression of key signaling nodes.
- This preclinical study supports the clinical investigation of combined rapamycin and trametinib for NSCLC treatment.
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