Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma

Kumar, Shaji; LaPlant, Betsy; Chng, Wee Joo; Zonder, Jeffrey A.; Callander, Natalie S.; Fonseca, Rafaël; Fruth, Briant; Roy, Vivek; Erlichman, Charles; Stewart, A. Keith

doi:10.1182/blood-2014-05-573741

Cited by 211 publications

(189 citation statements)

References 22 publications

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“…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

163

116

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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

163

116

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“…Structurally, this could be attributed to the large amount of shared features among the CDK family, particularly at the ATPbinding pocket, where current inhibitor discovery efforts are focused on. These structural similarities cause CDK9 Multiple clinical trials for hematologic and solid tumors (Parry et al 2010, Desai et al 2013, Flynn et al 2013, Nemunaitis et al 2013, Kumar et al 2015, Baker et al 2016 (Joshi et al 2007, Manohar et al 2011, Mishra et al 2013 www.clinicaltrials.gov…”

Section: Development Of Pharmacological Inhibitors Of Cdk9 For Pcamentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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“…Dinaciclib (MK-7965, formerly SCH727965), a novel, selective CDK1-4/7/9 inhibitor with improved therapeutic index, was found to induce apoptosis in CLL cells (Johnson, et al 2012). It has already been tested in initial trials for solid tumours (Nemunaitis, et al 2013), myeloma (Kumar, et al 2015) 5 and refractory CLL (Flynn, et al 2015). Encouraging Phase I and II results provide a rationale for the use of dinaciclib alone or in combination with immunotherapies in CLL and lymphoma (Blachly, et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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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Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma

Abstract: Key Points Dinaciclib is a novel cdk inhibitor that demonstrates single agent activity in myeloma. Dinaciclib has a safety profile that is easily manageable.

Cited by 211 publications

References 22 publications

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

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

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

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

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