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

Abstract

Studies in targeting metabolism in cancer cells have shown the flexibility of cells in reprogramming their pathways away from a given metabolic block. Such behavior prompts a combination drug approach in targeting cancer metabolism, as a single compound may not address the tumor intractability. Overall, mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated as enabling metabolic escape in the case of a glycolysis block. From a library of compounds, the tyrosine kinase inhibitor ponatinib was screened to provide optimal reduction in metabolic activity in the production of adenosine triphosphate (ATP), pyruvate, and lactate for multiple myeloma cells; however, these cells displayed increasing levels of oxidative phosphorylation (OXPHOS), enabling them to continue generating ATP, although at a slower pace. The combination of ponatinib with the mTORC1 inhibitor, sirolimus, blocked OXPHOS; an effect also manifested in activity reductions for hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) glycolysis enzymes. There were also remarkably higher levels of reactive oxygen species (ROS) produced in mouse xenografts, on par with increased glycolytic block. The combination of ponatinib and sirolimus resulted in synergistic inhibition of tumor xenografts with no overt toxicity in treated mice for kidney and liver function or maintaining weight.

Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma

“…Moreover, as Uddin Md. Nazim et al [ 58 ] described the combination treatment of the tyrosine kinase inhibitor ponatinib and the mTORC1 inhibitor sirolimus significantly reduced xenograft MM model tumor growth and weight compared to mono-treatment without obvious toxicity induction such as liver and kidney function damage or bodyweight loss. In a phase I clinical trial of relapsed or refractory MM, the combination of the mTOR inhibitor everolimus and the immunomodulatory agent lenalidomide impressively prolonged the median overall survival of patients [ 59 ].…”

The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells

“…Autophagy upregulation driven by metabolic dysfunction may contribute to a common mechanism of resistance to chemotherapy and radiation by reducing apoptosis and acting as a pro-survival mechanism. Although autophagy induced by glucose dysfunction acts as a pro-survival mechanism, it remains controversial, as the autophagy inducer rapamycin shows treatment synergy with the metabolic inhibitor ponatinib against multiple myeloma [ 181 ].…”

Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy

“…Combination inhibits MM1.S cell viability [ 140 ] Everolimus mTORC1 Single drug blocks cell cycle, resulting in inhibition of cell proliferation [ 141 ] Everolimus + Trametinib Everolimus: mTORC1 Trametinib: MEK Combination shows synergistic toxicity in all RAS-dependent MM cell lines [ 113 ] Everolimus + BZ Everolimus: mTORC1 BZ: Proteasome inhibitor Synergistic cytotoxicity [ 142 ] Everolimus + Panobinostat Everolimus: mTORC1 Panobinostat: HDACi Synergistic cytotoxicity caused by DNA damage and proliferation suppression [ 143 ] Everolimus + entinostat Everolimus: mTORC1 Entinostat: HDACi Inhibits oncogenic MYC and activates the Cdkn2a tumor suppressor [ 144 ] Rapamycin + 17-AGG Rapamycin: mTORC1 17-AAG: HSP90 Synergistically inhibits cell proliferation and induces cell death. Combination also targets BM microenvironment, inhibiting angiogenesis and osteoclast formation [ 145 ] Rapamycin + Ponatinib Rapamycin: mTORC1 Ponatinib: Tyrosine kinase Drug combination blocks OXPHOS and reduces activity of glycolytic enzymes, resulting in synergistic reduction of tumor xenografts without overt toxicity [ 146 ] TAK-228 mTORC1/2 TAK-228 suppresses survival of MM cell lines and overcomes the BMSC effects [ 147 ] pp242 mTORC1/2 pp242 leads to stronger cytotoxicity on MM cells and reduces the angioge...…”

“…As mentioned above, one of the mechanisms by which cancer cells can flexibly reprogram their pathways away from specific metabolic blockages is activation of mTOR. Combination of the tyrosine kinase inhibitor ponatinib and rapamycin therefore impaired the production of ATP required for cell proliferation by targeting glycolytic reprogramming and residual OXPHOS [ 146 ].…”