AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Keeton, Erika Krasnickas; McEachern, Kristen; Dillman, Keith; Palakurthi, Sangeetha; Cao, Yuntai; Grondine, Michael; Kaur, Surinder; Wang, Suping; Chen, Yuching; Wu, Allan; Shen, Minhui; Gibbons, Francis D.; Lamb, Michelle L.; Zheng, Xiaolan; Stone, Richard; DeAngelo, Daniel J.; Platanias, Leonidas C.; Dakin, Les A.; Chen, Huawei; Lyne, Paul; Huszar, Dennis

doi:10.1182/blood-2013-04-495366

Cited by 215 publications

(219 citation statements)

References 37 publications

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“…1A). Basal cell line PIM1 mRNA expression tends to be higher in sensitive lines, as previously shown at the protein level (8), underlying the importance of compound target expression alongside the interplay with genetic alterations for sensitivity. However, cells harboring pathway relevant genetic alterations or overexpressing PIM exhibit varied response to treatment, calling for a deeper examination of the cell signaling relating genotype to phenotype to provide a better understanding of the molecular dependencies underlying PIM inhibitor sensitivity in AML cell lines.…”

Section: Aml Cell Lines Show Differential Sensitivity To Pim Inhibitionsupporting

confidence: 48%

“…This is true in acute myeloid leukemia (AML), where patients may harbor somatic mutations in a number of potential oncogenes, including FLT3, MLL, TYK2, FGFR1, PDGFRA, IDH1, DNMT3A, affecting expression of downstream signaling for example through PIM kinases (5-7). FLT3 internal tandem duplications (FLT3-ITD) and PIM overexpression are associated with poor prognosis in AML patients, motivating the development of small molecule inhibitors targeting these proteins (8,9). Incomplete signaling inhibition or the presence of multiple molecular alterations that reduce a tumors dependency on any one target may result in drug resistance (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

et al. 2017

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Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within a histologically defined cancer subtype. This is especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity in molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences in signaling that help explain differences in drug response. Furthermore, they can suggest drug combinations to increase efficacy and combat acquired resistance. Here, we experimentally tested dynamic proteomic changes and phenotypic responses in diverse AML cell lines treated with pan-PIM kinase inhibitor and fms-related tyrosine kinase 3 (FLT3) inhibitor as single agents and in combination. We constructed cell-specific executable models of the signaling axis, connecting genetic aberrations in FLT3, tyrosine kinase 2 (TYK2), platelet-derived growth factor receptor alpha (PDGFRA), and fibroblast growth factor receptor 1 (FGFR1) to cell proliferation and apoptosis via the PIM and PI3K kinases. The models capture key differences in signaling that later enabled them to accurately predict the unique proteomic changes and phenotypic responses of each cell line. Furthermore, using cell-specific models, we tailored combination therapies to individual cell lines and successfully validated their efficacy experimentally. Specifically, we showed that cells mildly responsive to PIM inhibition exhibited increased sensitivity in combination with PIK3CA inhibition. We also used the model to infer the origin of PIM resistance engineered through prolonged drug treatment of MOLM16 cell lines and successfully validated experimentally our prediction that this resistance can be overcome with AKT1/2 inhibition.

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Section: Aml Cell Lines Show Differential Sensitivity To Pim Inhibitionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

et al. 2017

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“…Of note, similar results were obtained with EOL1, KG1, OCI-M1, HL60, and OCI-M2 cell lines in a recent publication using AZD1208, another pan-PIM kinase inhibitor. 31 The remaining 10 cell lines did not consistently achieve more than 70% inhibition at the highest concentration (3 mM) across the 3 PIM inhibitors tested and were categorized as intermediates (supplemental Figure 1). For all subsequent analyses, we intentionally focused exclusively on responder and nonresponder cell lines to maximize the chance of acquiring robust biological signals.…”

Section: Identification Of Aml Cell Lines Sensitive To the Inhibitionmentioning

confidence: 99%

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Guo

Wang

Zhang

et al. 2014

Blood

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Key Points• CD25 is a predictive biomarker for sensitivity to PIM inhibitors in AML cells.• PIM inhibitors may prolong overall/relapse-free survival through attenuating STAT5 activation and destabilizing MYC in CD25 1 AML cells.Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in

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“…We also found that HTLV-I cell lines harbored high levels of Pim1, but exogenous expression of viral proteins, Tax and HBZ, did not appreciably alter Pim1 expression (supplemental Figure 4C). To confirm the biological relevance of Pim1, we investigated the effect of Pim1 inhibitors, SMI-4a 24 and AZD1208, 25 on ATL cells. Treatment with either SMI-4a or AZD1208 was associated with a significant reduction in cell proliferation ( Figure 6C-D), independently confirmed by XTT assays ( Figure 6E-F and supplemental Figure 4D-F).…”

Section: Pim1 Is Constitutively Activated In Atl Cells and Targetingmentioning

confidence: 99%

“…AZD1208 has been shown to be effective in reducing tumor growth in mice harboring AML tumors. 25 In summary, re-expression of miR-124a in a murine model of ATL revealed a critical function of the STAT3/ Pim1 signaling axis in HTLV-I-transformed ATL cells. Constitutive activation of the Pim1 pathway is a promising novel therapeutic target for ATL.…”

mentioning

confidence: 99%

Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

Bellon

Lü

Nicot

2016

Blood

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AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Cited by 215 publications

References 37 publications

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

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