Is there a cloud in the silver lining for imatinib?

Paterson, Sarah; Smith, Kevin D.; Holyoake, Tessa L.; Jørgensen, Heather G.

doi:10.1038/sj.bjc.6600828

Cited by 25 publications

(15 citation statements)

References 35 publications

(31 reference statements)

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“…Most patients treated with Gleevec s respond to the drug and have a virtually complete cytogenetic responses (Druker et al, 1996;Mauro and Druker, 2001). However, In the majority of patients RT-PCR detects the fusion transcript in the patients' bone marrow cells suggesting that this therapy may not be curative (Paterson et al, 2003). In some patients in remission and negative for the translocation by fluorescent in situ hybridization (FISH) on unfractionated bone marrow, Bhatia et al (2003) demonstrated the presence of the BCR/ABL fusion by FISH analysis in the between 6.5 and 13% of their CD34 þ progenitor cells.…”

Section: Do Oncogenic Mutations Affect Cscs Nontumorigenic Progeny mentioning

confidence: 99%

Self-renewal and solid tumor stem cells

2004

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Section: Do Oncogenic Mutations Affect Cscs Nontumorigenic Progeny mentioning

confidence: 99%

Self-renewal and solid tumor stem cells

2004

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“…With progression to blast crisis, the malignant clones acquire additional genetic mutations, including trisomy 8, isochromosome I (17q), and trisomy 19. 30 Thus, the therapeutic window for cure is early in disease.…”

Section: Commentmentioning

confidence: 99%

Unexplained Hypereosinophilia and the Need for Cytogenetic and Molecular Genetic Analyses

Smith¹,

Jacobson²,

Hamza³

et al. 2004

Arch Dermatol

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“…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.…”

mentioning

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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Is there a cloud in the silver lining for imatinib?

Cited by 25 publications

References 35 publications

Self-renewal and solid tumor stem cells

Self-renewal and solid tumor stem cells

Unexplained Hypereosinophilia and the Need for Cytogenetic and Molecular Genetic Analyses

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

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