Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia

Wang, Lisheng; Wang, Jie; Blaser, Bradley W.; Duchemin, Anne‐Marie; Kusewitt, Donna F.; Liu, Tom; Caligiuri, Michael A.; Briesewitz, Roger

doi:10.1182/blood-2007-02-071266

Cited by 121 publications

(105 citation statements)

References 32 publications

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“…In addition, evolution to true resistance to extended CDK4/6 inhibition in tumor models may be critically dependent on loss of Rb function, as Rb deficiency has been observed to increase the levels of E2F-target genes cyclins A and E. These cyclins are requisite for CDK2 function, and their deregulation may ultimately provide a mechanism to circumvent CDK4/6 dependency, facilitating the acquisition of a proliferative cell-cycle driven by CDK2. This phenomenon has been observed in AML cell lines deficient for CDK4/6 activity, wherein loss of the CKI p27 Kip1 was able to promote phosphorylation of histone-H1 by CDK2 (Wang et al, 2007). Presumably, the lack of Rb may relieve the requirement for signaling through the CDK4/6 axis, and thus facilitate the acquisition of a proliferative cycle driven by CDK2.…”

Section: Discussionmentioning

confidence: 80%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

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Section: Discussionmentioning

confidence: 80%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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“…Acquired resistance to this drug may arise through activation of CDK2. 41,63 Another side effect of PD0332991 treatment could be the acquisition of a more invasive phenotype as observed in pancreatic cancer cell lines. 51 The clinical efficacy of PD0332991 and other CDK4/6 inhibitors, either as a monotherapy or in combination with various other drugs, was until now only tested in discontinuous treatments with one week off treatment every 2 or 3 weeks (clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

et al. 2014

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“…Wang et al [153] (2007) also found in patients with AML that downregulated CCND2 and CCND3 results in dephosphorylation of phospho retinoblastoma protein and induction of G(1) cell cycle arrest. These findings suggest that CCND2 may also be downregulated in AML in association with the upregulation of miR133a and miR1 levels, similar to multiple myeloma.…”

Section: Upregulated Myomirs In Cancermentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

138

132

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MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/ tissue regeneration/tissue inflammation responses, and cancer development. Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the "myomiRs". The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables. REVIEW

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Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia

Abstract: Entry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the

Cited by 121 publications

References 32 publications

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

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