Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase

Colamonici, Marco; Blyth, Gavin T.; Saleiro, Diana; Szilard, Amy; Bliss-Moreau, Meghan; Giles, Francis J.; Altman, Jessica K.; Beauchamp, Elspeth M.; Platanias, Leonidas C.

doi:10.18632/oncotarget.3509

Cited by 16 publications

(21 citation statements)

References 46 publications

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“…2,3,8,9 This has led to the development of catalytic mTOR inhibitors, which inhibit both mTORC1 and mTORC2, and combinatorial strategies using inhibitors that target PI3K, autophagy, and MAPK pathways. [9][10][11][12][13][14][15][16] However, none of these approaches have been approved for clinical use thus far, in part, due to limited responses or dose limiting toxicity. 2,[17][18][19][20] Therefore, it is crucial to discover new elements and effectors of the mTOR pathway that could be therapeutically targeted.…”

Section: Introductionmentioning

confidence: 99%

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Beauchamp

Abedin

Radecki

et al. 2019

Blood

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Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8. Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6. Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.

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Section: Introductionmentioning

confidence: 99%

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Beauchamp

Abedin

Radecki

et al. 2019

Blood

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“…The development of specific PI3K and MEK inhibitors for clinical oncology affords an opportunity to dissect these pathways. We hypothesized that PI3K, and possibly MEK, inhibition might selectively inhibit conventional CD4 + and CD8 + lymphocytes compared with Tregs.…”

Section: Introductionmentioning

confidence: 99%

Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways

Zwang

Zhang

Germana

et al. 2016

American Journal of Transplantation

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Phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated (MEK) signaling are central to the survival and proliferation of many cell types. Multiple lines of investigation in murine models have shown that control of the PI3K pathway is particularly important for regulatory T cell (Treg) stability and function. PI3K and MEK inhibitors are being introduced into the clinic, and we hypothesized that pharmacologic inhibition of PI3K, and possibly MEK, in mixed cultures of human mononuclear cells would preferentially affect CD4+ and CD8+ lymphocytes compared with Tregs. We tested this hypothesis using four readouts: proliferation, activation, functional suppression, and signaling. Results showed that Tregs were less susceptible to inhibition by both δ and α isoform–specific PI3K inhibitors and by an MEK inhibitor compared with their conventional CD4+ and CD8+ counterparts. These studies suggest less functional reliance on PI3K and MEK signaling in Tregs compared with conventional CD4+ and CD8+ lymphocytes. Therefore, the PI3K and MEK pathways are attractive pharmacologic targets for transplantation and treatment of autoimmunity.

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“…Assays were performed as previously described (Beauchamp et al., , ; Colamonici et al., ; Kosciuczuk et al., ). Briefly, 300‐500 U937 or MV4‐11 cells were plated in methylcellulose (MethoCult™ H4434 Classic w/o EPO, Stem Cell Technologies) and grown for 7 days to assess the effects of drugs on leukemic progenitor (CFU‐L) colony formation.…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening

et al. 2019

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Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.

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Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase

Cited by 16 publications

References 46 publications

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways

Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening

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