Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

Lindblad, Oscar; Cordero, Eugenia; Puissant, Alexandre; Macaulay, Lucy; Ramos, Azucena; Kabir, Nuzhat N.; Sun, Jianmin; Vallon‐Christersson, Johan; Haraldsson, Karin; Hemann, Michael T.; Borg, Åke; Levander, Fredrik; Stegmaier, Kimberly; Pietras, Kristian; Rönnstrand, Lars

doi:10.1038/onc.2016.41

Cited by 102 publications

(68 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The PI3K/Akt/mTOR pathway is also a promising target in AML with FLT3 mutations. mTOR, downstream of FLT3, is upregulated in FLT3 inhibitor-resistant AML cells and promotes cell survival and proliferation [68]; inhibition of both mTOR and FLT3 leads to synergistic suppression of cell proliferation [69]. A clinical trial is evaluating the safety of the mTOR inhibitor everolimus (Afinitor®, Novartis) in combination with midostaurin (NCT00819546).…”

Section: Flt3 Inhibitor Resistancementioning

confidence: 99%

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Larrosa-García

Baer

2017

Molecular Cancer Therapeutics

247

209

View full text Add to dashboard Cite

The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches.

show abstract

Section: Flt3 Inhibitor Resistancementioning

confidence: 99%

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Larrosa-García

Baer

2017

Molecular Cancer Therapeutics

247

209

View full text Add to dashboard Cite

show abstract

“…In these models, inhibition of the mTOR pathway can rescue the sensitivity of these cells to both FLT3 inhibitors and anthracyclines 28 . Similarly, cells resistant to Sorafenib continue to have an active mTOR/PI3K/Akt pathway even in the presence of effective FLT3 inhibition 29,30 , and mTOR inhibitors can re-sensitize the blasts to TKI 29 . Some FLT3-ITD point mutations (D627E) can induce expression of Mcl-1 (a Bcl-2 family member) independent of kinase activity via a conformational change that favors Grb-2 docking 31 .…”

Section: Emergence Of Resistancementioning

confidence: 99%

“…To this end, a dual inhibitor of Akt/FLT3-ITD, A674563, can overcome FLT3 ligand induced drug resistance in vitro and in xenograft models 44 . Similarly, mTOR inhibition can sensitize cells to FLT3 inhibition 28 likely via targeting signaling downstream of PI3K 29 . An alternative approach that showed preclinical activity is to directly target Bcl2.…”

Section: Strategies To Prevent Development Of Resistance or To Sensitmentioning

confidence: 99%

Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

Ghiaur

Levis

2017

Hematology/Oncology Clinics of North America

View full text Add to dashboard Cite

Synopsis The presence of FLT3 mutations in AML carries a particularly poor prognosis making the development of FLT3 inhibitors an imperative goal for these patients. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the imminent approval by the FDA of FLT3 inhibitors for the treatment of AML. Unfortunately, the initial success stories have been rapidly followed by the emergence of clinical resistance. While novel FLT3 inhibitors are actively being developed, studies into mechanisms of resistance to these drugs raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease in this AML.

show abstract

“…MLN0128 is a novel, recently developed mTOR kinase inhibitor that can disrupt survival signaling and triggers apoptosis in AML stem and AML progenitor cells (8). Abnormal mTOR activity contributes to chemotherapy resistance, and aberrant activation of the PI3K/mTOR pathway promotes sorafenib resistance in AML cells (9). …”

Section: Introductionmentioning

confidence: 99%

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

Tao

et al. 2017

Oncology Reports

View full text Add to dashboard Cite

Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy-inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.

show abstract

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

Cited by 102 publications

References 47 publications

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

Contact Info

Product

Resources

About