Tyrosine Kinase Inhibition in Leukemia Induces an Altered Metabolic State Sensitive to Mitochondrial Perturbations

Alvarez-Calderon, Francesca; Gregory, Mark A.; Pham-Danis, Catherine; DeRyckere, Deborah; Stevens, Brett M.; Zaberezhnyy, Vadym; Hill, Amanda A.; Gemta, Lelisa; Kumar, Amit; Kumar, Vijay; Wempe, Michael F.; Pollyea, Daniel A.; Jordan, Craig T.; Serkova, Natalie J.; Graham, Douglas K.; DeGregori, James

doi:10.1158/1078-0432.ccr-14-2146

Cited by 57 publications

(71 citation statements)

References 48 publications

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“…ITD leukemias (22). These data demonstrated synergistic effects between oligomycin and imatinib or quizartinib in eradicating leukemic cells, demonstrating that, as we showed in pancreatic cancer, OXPHOS inhibition is synthetically lethal with the extinction of the oncogenic signaling in leukemias.…”

Section: Tumorigenic Cells Are Dependent On Mitochondrial Respirationsupporting

confidence: 70%

“…As elegantly demonstrated by the authors, tigecycline interfered with mitochondrial translation and depleted mitochondrial subunits of respiratory complexes, resulting in respiratory inhibition (21). In this context, interesting work was recently published highlighting the combinatorial effects exerted by oligomycin, a complex V mitochondrial inhibitor, and small-molecule tyrosine kinase inhibitors in BCR-ABL and FLT3ITD leukemias (22). These data demonstrated synergistic effects between oligomycin and imatinib or quizartinib in eradicating leukemic cells, demonstrating that, as we showed in pancreatic cancer, OXPHOS inhibition is synthetically lethal with the extinction of the oncogenic signaling in leukemias.…”

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confidence: 67%

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Tumors and Mitochondrial Respiration: A Neglected Connection

2015

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For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. However, a growing body of evidence is now challenging this assumption, and also implying that tumors are metabolically less homogeneous than previously supposed. A small subpopulation of slow-cycling cells endowed with tumorigenic potential and multidrug resistance has been isolated from different tumors. Deep metabolic characterization of these tumorigenic cells revealed their dependency on mitochondrial respiration versus glycolysis, suggesting the existence of a common metabolic program active in slowcycling cells across different tumors. These findings change our understanding of tumor metabolism and also highlight new vulnerabilities that can be exploited to eradicate cancer cells responsible for tumor relapse. Cancer Res; 75(18); 3687-91. Ó2015 AACR. Dysfunctional Mitochondria and CancerSpeaking on the origins of cancer, Otto Warburg stated, "When the respiration of body cells has been irreversibly damaged, cancer cells by no means immediately result" (1). Warburg was Director of the Max Planck Institute for Cell Physiology when he gave this seminal lecture, and he was likely unaware of the profound impact his work on "aerobic glycolysis" would have had for the next several decades. Today mitochondria, or "grana" as they were named in Warburg's time, are much more than the bioenergetics "powerhouse" of the cell; rather, they are now regarded as important biosynthetic and signaling organelles (2). Despite a more comprehensive understanding of the complex physiology of mitochondria, the relationship between mitochondria and cancer cells continues to be perceived very simplistically: cancer cells have diminished capacity for oxidative phosphorylation (OXPHOS) due to dysfunctional mitochondria. However, the full extent of this impairment, as well as its significance, is not yet completely understood (3). Mitochondrial DNA mutations and their significanceAn obvious place to look for clues regarding mitochondrial defects in cancer is the mitochondrial genome. Despite the fact that mutations in mitochondrial DNA (mtDNA) genes encoding subunits of respiratory complexes have been found in the majority of tumors (3, 4), their high frequency and diversity have made it difficult to pinpoint their role in cancer. Moreover, the functional interpretation of many of the mutations remains ambiguous, and in many cases it remains unclear whether they represent gain of function mutations, neutral polymorphisms or even artifacts (4-6). To date, very few studies have demonstrated a direct relationship between recurrent mtDNA mutations and tumor maintenance (7,8). However, it is generally accepted that mtDNA mutations are responsible for the induction of reactive oxygen species (ROS) at the expense of a less-efficient electron transfer chain (ETC). ROS, in turn, activate several signaling pathways critical for tumor growth and maintenance (9). Ultimately, OXPHOS activity is not suppressed in ...

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Section: Tumorigenic Cells Are Dependent On Mitochondrial Respirationsupporting

confidence: 70%

supporting

confidence: 67%

Tumors and Mitochondrial Respiration: A Neglected Connection

2015

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“…Similar OXPHOS-addicted subpopulations with TIC properties have also been identified in other cancer types, such as leukemia and melanoma (Lagadinou et al 2013;Vazquez et al 2013). It is notable that OXPHOS inhibition works synergistically with targeted therapies directed against driving oncogenes (Haq et al 2013;Alvarez-Calderon et al 2015). Thus, it is possible that an effective strategy to eliminate both bulk cancer cells and TICs in PDAC would combine targeted therapy directed against the oncogenic KRAS pathway such as MEK as well as drugs that directly inhibit mitochondrial respiration (Viale et al 2015).…”

Section: Intratumoral Metabolic Heterogeneitymentioning

confidence: 75%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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“…After expansion in vivo, the secondary leukemia was harvested from the spleen and bone marrow and subsequently transplanted into 6-to 10-wk-old female NSG mice for drug treatment; 5 × 10 5 cells were injected i.v., and treatment started when peripheral blast count was between 4% and 17% (mean was 9.1-10% for all groups). AC220, which was synthesized and prepared as previously described (20), was delivered once daily p.o. Elesclomol was dissolved in 10% DMSO/ 18% (vol/vol) Kolliphor and delivered once daily i.v.…”

Section: Methodsmentioning

confidence: 99%

“…S6D). Notably, increased mitochondrial ROS is not a universal consequence of all TKIs, as treatment of K562 CML with high doses of the BCR-ABL TKI imatinib that are known to cause apoptosis (20,21) failed to cause substantial induction of mitochondrial ROS (Fig. S6E).…”

Section: Glutathione Metabolism Is Impaired On Flt3 Inhibition and Fumentioning

confidence: 99%

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Gregory

D’Alessandro

Alvarez-Calderon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.A cute myeloid leukemia (AML) is a hematological cancer that is characterized by the aberrant growth of myeloid progenitor cells with a block in cellular differentiation. AML is the most common adult acute leukemia and accounts for ∼20% of childhood leukemias. Although frontline treatment of AML with cytotoxic chemotherapy achieves high remission rates, 75-80% of patients will either not respond to or will relapse after initial therapy, and most patients will die of their disease (1, 2). Thus, more effective and less toxic therapies for AML are required. The promise of molecularly targeted cancer therapies has generated much excitement with the remarkable clinical success of the small molecule tyrosine kinase inhibitors (TKIs) targeting the oncogenic kinase BCR-ABL for the treatment of chronic myeloid leukemia (3). However, targeted approaches for the treatment of AML have not yet yielded major successes.In AML, aberrant signal transduction drives the proliferation and survival of leukemic cells. Activated signal transduction occurs through genetic alterations of signaling molecules such as FLT3, KIT, PTPN11, and members of the RAS family (4, 5). Given the successful development and utilization of numerous TKIs, the FLT3 receptor tyrosine kinase has emerged as a promising target for the treatment of AML. Indeed, activating mutations in FLT3 are one of the most frequently observed genetic defects in AML and are comprised predominantly of internal tandem duplication (ITD) mutations in the juxtamembrane domain (6). FLT3-ITD mutations are associated with poor prognosis, including increased relapse rate, decreased disease-free survival, and poor overall survival (5,7,8). The cl...

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Tyrosine Kinase Inhibition in Leukemia Induces an Altered Metabolic State Sensitive to Mitochondrial Perturbations

Cited by 57 publications

References 48 publications

Tumors and Mitochondrial Respiration: A Neglected Connection

Tumors and Mitochondrial Respiration: A Neglected Connection

Genetics and biology of pancreatic ductal adenocarcinoma

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

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