The CDK inhibitors in cancer research and therapy

Cicenas, Jonas; Valius, Mindaugas

doi:10.1007/s00432-011-1039-4

Cited by 222 publications

(183 citation statements)

References 81 publications

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“…This effect was noted to be proteasome-independent, although the molecular mechanism was not delineated (55). Cdk inhibitors have long been of interest as anticancer agents (57). Our results lend mechanistic support for the use of Cdk1 inhibitors in tumors with high levels of HIF-1α, given their dual effects as inhibitors of HIF-1α transcriptional activity and of cell-cycle progression.…”

Section: (D and E) Mouse Mefs Fromsupporting

confidence: 67%

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi¹,

Gilkes

Hu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions. cell proliferation | chaperone mediated autophagy | lysosome

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Section: (D and E) Mouse Mefs Fromsupporting

confidence: 67%

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi¹,

Gilkes

Hu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, roscovitine (seliciclib) has been evaluated in the phase I setting in patients with solid tumors, with minimal disease stabilization seen in monotherapy [23]. It inhibits CDKs 1, 2, 5, and 7 but is a poor inhibitor of CDK4/6 [24]. Abbreviations: CDK4/6, cyclin-dependent kinases 4 and 6; E2F, E2 transcription factor; P, phosphate group; Rb, retinoblastoma tumor suppressor protein.…”

Section: The Cell Cycle and The Balance Between Senescence And Prolifmentioning

confidence: 99%

The Role of CDK4/6 Inhibition in Breast Cancer

2015

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Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptorpositive (ER1) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion.We describe the applicationofsuch therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improvingthe outcomes of patients with ER1 breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting. The Oncologist 2015;20:483-490Implications for Practice: Cyclin-dependent kinases (CDKs) interact with cyclin D proteins to play an integral role in cell cycle progression and represent attractive therapeutic targets in many tumors, including breast cancer. A number of highly selective inhibitors of CDK4 and CDK6 (CDK4/6) are currently in clinical trial development with one agent recently approved by the U.S. Food and Drug Administration for the treatment of advanced ER+, HER2-negative breast cancer.This article reviews the role of CDK4/6 in tumorigenesis and summarizes the clinical trial experience with inhibitors of these kinases in breast cancer. Key efficacy and toxicity data from the clinical trial experience to date have been reviewed. The planned further expansion of their role in breast cancer therapies and potential concerns regarding combinations with other therapies are addressed.

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“…In fact, some of the most commonly used antitumor drugs, including anthracyclines, nucleoside analogs, platinum salts, taxanes, and vinca alkaloids, exert their effects through disrupting various stages of the cell cycle. 2 Additionally, there are many compounds in clinical development, such as cyclin dependent kinase inhibitors 3,4 and novel microtubule disrupting agents 5,6 that also exert their antitumor effects by disrupting the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

et al. 2015

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PURPOSE:Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells -G 1 , S, and G 2 /M.METHODS: Temsirolimus (G 1 inhibitor), topotecan (S inhibitor), and bortezomib (G 2 /M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m 2 IV D1, 8; and bortezomib 0.9 mg/m 2 IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G 2 /M and S phases to G 1 phase and the quiescent G 0 phase. Eighteen percent of subjects (11/62) achieved partial response (n D 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n D 9).

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The CDK inhibitors in cancer research and therapy

Cited by 222 publications

References 81 publications

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

The Role of CDK4/6 Inhibition in Breast Cancer

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

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