mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma

Area of Science:

• Oncology
• Cancer Metabolism
• Drug Discovery

Background:

• Cancer cells exhibit metabolic flexibility, reprogramming pathways to evade single-agent drug treatments.
• Mammalian target of rapamycin complex 1 (mTORC1) signaling facilitates metabolic escape from glycolysis inhibition.
• Targeting cancer metabolism requires combination therapies to overcome tumor resistance.

Purpose of the Study:

• To investigate the efficacy of combining ponatinib, a tyrosine kinase inhibitor, with an mTORC1 inhibitor (sirolimus) against multiple myeloma.
• To evaluate the impact of this combination on cellular metabolism, including glycolysis and oxidative phosphorylation (OXPHOS).
• To assess the in vivo anti-tumor activity and toxicity of the drug combination in mouse xenograft models.

Main Methods:

• Screening of compounds to identify inhibitors of cancer cell metabolism.
• Treatment of multiple myeloma cells with ponatinib to assess metabolic activity.
• Combination treatment with ponatinib and sirolimus to evaluate effects on ATP, pyruvate, lactate, and OXPHOS.
• Assessment of hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) enzyme activity.
• In vivo studies using mouse xenografts to measure tumor growth inhibition, reactive oxygen species (ROS) levels, and toxicity.

Main Results:

• Ponatinib alone reduced metabolic activity (ATP, pyruvate, lactate) but increased OXPHOS in multiple myeloma cells.
• The combination of ponatinib and sirolimus effectively blocked OXPHOS and reduced glycolysis enzyme activity (HK2, GPI).
• Combination treatment led to increased ROS production in mouse xenografts, correlating with glycolytic blockade.
• Synergistic inhibition of tumor xenografts was observed with the ponatinib-sirolimus combination.
• No overt toxicity was observed in treated mice regarding kidney/liver function or body weight.

Conclusions:

• Combination therapy with ponatinib and sirolimus offers a synergistic approach to inhibit multiple myeloma tumor growth.
• This combination effectively targets key metabolic pathways (glycolysis and OXPHOS) in cancer cells.
• The dual-drug strategy demonstrates a favorable safety profile in preclinical models, warranting further investigation.