The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma

Area of Science:

• Oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Altered cellular metabolism is a key characteristic of cancer, driving tumor growth and providing targets for novel cancer therapies.
• Lung squamous cell carcinoma (SCC) exhibits metabolic adaptations that contribute to its progression and therapeutic resistance.
• Mammalian target of rapamycin (mTOR) signaling plays a crucial role in regulating cellular metabolism and growth in cancer.

Purpose of the Study:

• To investigate metabolic adaptations in lung squamous cell carcinoma (SCC) for potential therapeutic targeting.
• To identify molecular mechanisms underlying resistance to mTOR inhibition in lung SCC.
• To explore the potential of combined metabolic therapies for cancer treatment.

Main Methods:

• In vivo metabolic profiling of lung SCC models.
• Molecular analysis including protein level assessments (e.g., phospho-GSK3α/β).
• Evaluation of therapeutic responses to mTOR inhibitors and glutaminase inhibitors (e.g., CB-839) in preclinical models.

Main Results:

• Lung SCC adapts to mTOR inhibition and glycolysis suppression via the GSK3α/β signaling pathway, leading to increased glutaminolysis.
• Phospho-GSK3α/β protein levels can predict response to single-agent mTOR inhibition therapy.
• Combination therapy with an mTOR inhibitor and the glutaminase inhibitor CB-839 overcomes therapeutic resistance in lung SCC.
• A conserved metabolic signature in hypermetabolic tumors suggests potential for combined metabolic therapies.

Conclusions:

• The GSK3α/β signaling pathway is a critical mediator of metabolic adaptation and resistance in lung SCC.
• Combined targeting of mTOR and glutaminase represents a promising therapeutic strategy for lung SCC and potentially other hypermetabolic tumors.
• Metabolic profiling and specific molecular markers can inform patient selection and treatment strategies for metabolic cancer therapies.