Oncogenic drivers and mitochondrial dependency

Alvarez-Calderon, Francesca; DeGregori, James

doi:10.18632/aging.100734

Cited by 2 publications

(3 citation statements)

References 5 publications

(11 reference statements)

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“…Consistent activation of the PI3K/Akt/mTOR pathway by BCR-ABL1 also increases glucose metabolism in leukemic cells [ [9] , [10] , [11] ]. In light of these observations, it is not surprising that the exposure to oncogenic “driver” inhibitors such as BRAFV600E inhibitors [ 7 , 8 ] or BCR-ABL1 inhibitors [ 11 , 12 ] dramatically reduces glucose uptake and glycolysis to promote cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

“…A large body of evidence indicates that mitochondrial oxidative metabolic pathways play a crucial role in cancer development, particularly to immediately compensate for glucose deprivation. This dependence on mitochondrial oxidative metabolism allows cells to avoid cell death induced by MAPK inhibitors [ 7 , 13 ] or TKI [ 6 , 12 ]. Moreover, CML stem cells are particularly sensitive to mitochondrial oxidative metabolism inhibitors [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells

Trinh¹,

Khamari²,

Fovez³

et al. 2022

Molecular Metabolism

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Objective Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective cure for chronic myeloid leukemia (CML) patients and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells (LSC) indicate that new therapeutic strategies are needed to control LSC and to prevent relapse. In this study we investigated the metabolic pathways responsible for CML surviving to imatinib exposure and its potential therapeutic utility to improve the efficacy of TKI against stem-like CML cells. Methods Using complementary cell-based techniques, metabolism was characterized in a large panel of BCR-ABL+ cell lines as well as primary CD34+ stem-like cells from CML patients exposed to TKI and L-Asparaginases. Colony forming cell (CFC) assay and flow cytometry were used to identify CML progenitor and stem like-cells. Preclinical models of leukemia dormancy were used to test the effect of treatments. Results Although TKI suppressed glycolysis, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase or Erwinase without inducing predominant CML cell death. However, clinically relevant concentrations of TKI render CML cells susceptible to Kidrolase. The combination of TKI with Lasparaginase reactivates the intinsic apoptotic pathway leading to efficient CML cell death. Conclusion Targeting glutamine metabolism with the FDA-approved drug, Kidrolase in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating stem-like CML cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells

Trinh¹,

Khamari²,

Fovez³

et al. 2022

Molecular Metabolism

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show abstract

“…Interestingly, the dependence on mitochondrial oxidative metabolism allows cells to avoid cell death induced by MAPK inhibitors [7] or TKI [12]. Moreover, CML stem cells are particularly sensitive to mitochondrial oxidative metabolism inhibitors [13].…”

Section: Introductionmentioning

confidence: 99%

Antimetabolic cooperativity with the clinically approved kidrolase and tyrosine kinase inhibitors to eradicate cml stem cells

Trinh

Khamari

Fovez

et al. 2020

Preprint

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Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective treatment for chronic myeloid leukemia (CML) and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells indicate that new therapeutic strategies are needed to prevent molecular relapses. We investigated the metabolic pathways responsible for CML surviving to Imatinib exposure and its potential therapeutic utility to improve the efficiency of TKI against CML stem cells. Using complementary cell-based techniques, we demonstrated that TKI suppressed glycolysis in a large panel of BCR-ABL1 + cell lines as well as in primary CD34+ stem-like cells from CML patients. However, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase without inducing predominant CML cell death. Clinically relevant concentrations of TKI render CML progenitors and stem cells susceptible to Kidrolase. The combination of TKI with L-asparaginase reactivated the intinsic apoptotic pathway leading to efficient CML cell death. Thus, targeting glutamine metabolism with the clinically-approved drug Kidrolase, in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating CML stem cells.

show abstract

Oncogenic drivers and mitochondrial dependency

Cited by 2 publications

References 5 publications

Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells

Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells

Antimetabolic cooperativity with the clinically approved kidrolase and tyrosine kinase inhibitors to eradicate cml stem cells

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