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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.
Cancer Research
|November 18, 2015
Summary
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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