Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia

Sawai, Catherine M.; Freund, Jacquelyn; Oh, Phil; Ndiaye‐Lobry, Delphine; Bretz, Jamieson; Strikoudis, Alexandros; Genescà, Eulàlia; Trimarchi, Thomas; Kelliher, Michelle A.; Clark, Marcus R.; Soulier, Jean; Chen‐Kiang, Selina; Aifantis, Iannis

doi:10.1016/j.ccr.2012.09.016

Cited by 163 publications

(135 citation statements)

References 49 publications

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“…Cdk4/6 inhibitors also have pRB-independent effects, particularly when used at high concentrations. In contexts where deregulation of Cyclin D:Cdk4/6 kinases drives tumorigenesis, inhibition of these kinases can trigger cellular senescence or apoptosis (Fry et al 2004;Thangavel et al 2011;Choi et al 2012;Sawai et al 2012). Cdk4/6 inhibitors had modest effects when tested as a monotherapy in solid tumors (Flaherty et al 2012;Dickson et al 2013;Cadoo et al 2014;DeMichele et al 2015;Vaughn et al 2015).…”

Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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“…Cyclin D3 is an essential D-type cyclin for normal expansion of T-cell progenitors (18). Cyclin D2 and D3 have nonredundant roles in T-cell development (29). Cyclin D3 deficiency is sufficient to reduce susceptibility to T-cell malignancies.…”

Section: Inactivation Of Mtorc1 Prevents Oncogenic Kras-induced T-allmentioning

confidence: 99%

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Hoshii

Kasada

Hatakeyama

et al. 2014

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

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mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

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“…Due to this synthetic-lethal interaction between NOTCH1 overexpression and CDK6 inhibition, it was proposed that inhibiting the kinase activity of CDK6 in patients with NOTCH1-postive T-ALL is an attractive therapeutic strategy. [65][66][67] Furthermore, several studies on patients suffering from lymphomas have revealed chromosomal translocations and the consequent over-expression of CDK6 is a driving force for the disease. 68,69 Taken together, these findings strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia

Cited by 163 publications

References 49 publications

RB1: a prototype tumor suppressor and an enigma

RB1: a prototype tumor suppressor and an enigma

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Targeting CDK6 in cancer: State of the art and new insights

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