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

Abstract

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.

Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity

“…While asparaginase that reduces the availability of asparagine is a well-established therapy for ALL 118 , its effect on CML cells has recently been explored 119,120 . Strikingly, these studies confirmed that asparaginase similarly depletes glutamine, also essential for CML cells.…”

Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia

“…Trinh et al. also demonstrated that L-ASNase could inhibit the growth of CML cells, and the combination of L-ASNase and imatinib can significantly induce CML cell death by downregulating antiapoptotic factors such as Bcl-2 and upregulating proapoptotic factors such as Bim, and thereby eradicating CML stem cells ( 80 ). A recent study by Konhauser et al.…”

Alterations in cellular metabolisms after TKI therapy for Philadelphia chromosome-positive leukemia in children: A review

“…Anne Trinh et al. found that, after the treatment of IM, survived CML cells can continue to consume glutamine to create alphaKetoGlutarate, a TCA intermediate, that keeps the state of high mitochondrial oxidative metabolism ( 94 ). After that, they found that the combination of Kidrolase (an FDA-approved drug of L-asparaginase) and IM can deplete extracellular glutamine and therefore restrict mitochondrial metabolism.…”

“…In order to kill LSCs, Anne Trinh et al. also provided evidence that both glycolysis and glutamine-dependent mitochondrial metabolism required to be impaired ( 94 ). To prevent recurrence and achieve a longer OS of children, it may be an interesting therapeutic approach to eradicate LSCs by combining TKI and mitochondrial inhibitors.…”