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Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers
Milica Momcilovic1, Robert McMickle1, Evan Abt2
1Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
Abstract:
Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors.
Insights
Combining phenformin and MLN0128 shows promise for treating KRAS/LKB1-mutant non-small cell lung carcinoma (NSCLC). This strategy effectively targets lung adenocarcinomas and overcomes resistance in squamous cell carcinomas.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Inactivation of the Liver Kinase B1 (LKB1) tumor suppressor is common in non-small cell lung carcinoma (NSCLC).
- LKB1 inactivation activates mTOR complex 1 (mTORC1), making NSCLC sensitive to phenformin.
- KRAS and LKB1 gene comutations are found in a subset of NSCLC patients.
Purpose of the Study:
- To investigate the efficacy of combining phenformin with the mTOR inhibitor MLN0128 for treating NSCLC with KRAS/LKB1 comutations.
- To explore differential responses between lung adenocarcinoma and squamous cell carcinoma subtypes.
Main Methods:
- Utilized human NSCLC cell lines and genetically engineered mouse models.
- Administered combinatorial therapy of phenformin and MLN0128.
- Investigated resistance mechanisms involving the AKT-GSK signaling axis.
- Tested combination therapy with AKT inhibitor MK2206 to overcome resistance.
Main Results:
- Phenformin + MLN0128 demonstrated significant therapeutic responses in KRAS/LKB1-mutant NSCLC models, including adenocarcinomas and SCCs.
- Lung adenocarcinomas showed a strong response, while SCCs exhibited attenuated responses due to acquired resistance to mTOR inhibition.
- Resistance in SCCs was linked to modulation of the AKT-GSK signaling pathway.
- Combining mTOR and AKT inhibitors (MK2206) effectively inhibited squamous lung tumor growth and viability.
Conclusions:
- Combined phenformin and MLN0128 represents a potential personalized therapeutic strategy for KRAS/LKB1-mutant NSCLC.
- Targeting the AKT-GSK axis with MK2206 is crucial for overcoming resistance in squamous lung tumors.
- These findings offer a pathway for clinical translation in treating specific NSCLC subtypes.
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