Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor–chemotherapy combinations as an anticancer strategy for solid tumors

Johnson, Neil; Shapiro, Geoffrey I.

doi:10.1517/14728222.2010.525221

Cited by 96 publications

(87 citation statements)

References 114 publications

(138 reference statements)

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“…This revealed gene categories enriched for critical kinases and transcription factors required for both cell cycle progression and checkpoint cascades, including activation of the DDR (fold enrichment > 5, P < 0.05) (Supplemental Fig. S6A; Di Micco et al 2006;Cerqueira et al 2009;Tian et al 2009;Johnson and Shapiro 2010;Liu et al 2010;Shintomi et al 2015;Sivakumar and Gorbsky 2015). These genes, including AURKA, AURKB, BIRC5, CCNA2, CCNB2, CCNB1, CDC20, CDK1, CDK2, CHEK1, FOXM1, KIF20A, MAD2L1, NCAPG, Polo-like kinase 1 (PLK1), TOP2A, and UBE2C (examples displayed in Fig.…”

Section: Mll1 Directly Regulates the Expression Of Numerous Critical mentioning

confidence: 99%

MLL1 is essential for the senescence-associated secretory phenotype

et al. 2016

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Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces "SASP-like" inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS-or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression.

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Section: Mll1 Directly Regulates the Expression Of Numerous Critical mentioning

confidence: 99%

MLL1 is essential for the senescence-associated secretory phenotype

et al. 2016

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“…Rb is inactivated in multiple cancers, including in about 90% small-cell lung cancers (11,20,50), which are routinely treated with cisplatin. Combining cisplatin and CDK4/6 inhibitors during the treatment of these malignancies has the potential to reduce renal toxicities significantly without having cell-cycle-dependent antagonistic effects in cancer cells (20,68).…”

Section: Cdk4/6 Inhibitors As Adjunct Therapy During Cisplatin Treatmmentioning

confidence: 99%

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Pabla

Gibson

Buege

et al. 2015

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

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Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

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“…43 Moreover, Cdk2 might be a potential target for "synthetic lethal" chemotherapy, which exploits vulnerability to DNA damage-either caused by intrinsic mutations or induced by drugs-in cancer cells. 44 The availability of both transformed (HCT116) and non-transformed (RPE-hTERT) Cdk2…”

Section: Providing Safe Passage: Cdk2 Drives Cells Through the R Poinmentioning

confidence: 99%

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Merrick

Fisher

2012

Cell Cycle

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P rogression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs).For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemicalgenetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systemslevel organization of the cell cycle, for regulation of the restriction point and G 1 /S transition and for efforts to target Cdk2 therapeutically in human cancers.

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Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor–chemotherapy combinations as an anticancer strategy for solid tumors

Cited by 96 publications

References 114 publications

MLL1 is essential for the senescence-associated secretory phenotype

MLL1 is essential for the senescence-associated secretory phenotype

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

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