CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo

Gregory, Gareth P.; Hogg, Simon J.; Kats, Lev; Vidacs, Eva; Baker, Adele; Gilan, Omer; Lefebure, Marcus; Martin, Benjamin P.; Dawson, Mark A.; Johnstone, Ricky W.; Shortt, Jake

doi:10.1038/leu.2015.10

Cited by 118 publications

(121 citation statements)

References 15 publications

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“…This apoptosis correlated with suppression of CDK9 enzymatic activity and downregulation of previously identified MLL-AF9 target genes HoxA9 and Meis1, indicating CDK9 as an important mediator of the effect of dinaciclib. Consistent with prior reports in other malignancies (22)(23)(24), apoptosis induction by dinaciclib correlated with acute transcriptional downregulation of Mcl-1 and retroviral overexpression of Mcl-1 rescued dinaciclib-induced death of MLL-AF9-driven AML cells. Importantly, dinaciclib was efficacious in vivo in mice bearing human and mouse MLL-AF9-driven AMLs and very clearly outperformed a chemotherapeutic regimen involving a combination of cytarabine and doxorubicin.…”

Section: Introductionsupporting

confidence: 79%

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

et al. 2016

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Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclibinduced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. Cancer Res; 76(5); 1158-69. Ó2015 AACR.

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Section: Introductionsupporting

confidence: 79%

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

et al. 2016

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“…reports showing that MCL-1 expression was decreased by dinaciclib in various cancer cells (Chen, et al 2015, Fu, et al 2011, Gregory, et al 2015, Varadarajan, et al 2015. As shown in Figure 3F, we confirmed that dinaciclib inhibited both MCL-1 and BCL-xL in stimulated primary cells and MEC-1.…”

Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellssupporting

confidence: 74%

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

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Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.

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“…Through CDK9 inhibition, dinaciclib has been shown to downregulate the expression of the oncogene Myc, and several studies have demonstrated that Myc-driven tumors are especially sensitive to dinaciclib (43,66,67). Recently, Myc inactivation in tumor cells has been linked to downregulation of PD-L1 and CD47, molecules that normally would suppress both adaptive and innate antitumor responses (68).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we demonstrate that the CDK inhibitor dinaciclib (also known as MK-7965 and SCH727965) is capable of eliciting ICD. Dinaciclib is a potent CDK1, -2, -5, and -9 inhibitor that induces apoptosis in different tumor cells and has been shown to be clinically active in refractory chronic lymphocytic leukemia (38)(39)(40)(41)(42)(43)(44)(45)(46). These CDK targets regulate the cell cycle (CDK1, -2), control actin polymerization and neuronal function (CDK5), and regulate RNA-polymerase II (CDK9), and their repression can affect T cell proliferation and migration (47).…”

Section: Dinaciclib and Anti-pd1 Combination Therapy Inhibits Establimentioning

confidence: 99%

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

Hossain¹,

Javaid²,

Cai³

et al. 2018

Journal of Clinical Investigation

155

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CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo

Cited by 118 publications

References 15 publications

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

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