Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Dang, Fabin; Nie, Li; Zhang, Jin; Shimizu, Kouhei; Chu, Chengcai; Wu, Zhong; Fassl, Anne; Ke, Shizhong; Wang, Yuangao; Zhang, Jinfang; Zhang, Tao; Tu, Zhenbo; Inuzuka, Hiroyuki; Siciński, Piotr; Bass, Adam J.; Wei, Wenyi

doi:10.1038/s41467-021-25700-6

Cited by 25 publications

(20 citation statements)

References 39 publications

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“…Analogous synthetic lethal combinations have been proposed in clear cell renal cell carcinoma, where HIF2A stimulates Cyclin D transcription (Nicholson et al, 2019). Furthermore, other combinations have been identified that act via similar principles, such as CK1ε inhibition which represses SP1-mediated CDK6 transcription following CDK4/6 inhibition in breast cancer (Dang et al, 2021). The ability of cancer cells to transcriptionally upregulate Cyclin D-CDK4/6 activity via a variety of different routes, suggests that similar effective combinations await discovery in other tumour types.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Foy

Crozier

Pareri

et al. 2022

Preprint

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A long-term goal in cancer research has been to inhibit the cell cycle in tumour cells without causing toxicity in proliferative healthy tissues. The best evidence that this is achievable is provided by CDK4/6 inhibitors, which arrest the cell cycle in G1, are well-tolerated in patients, and are effective in treating ER+/HER2- breast cancer. CDK4/6 inhibitors are effective because they arrest tumour cells more efficiently than some healthy cell types and, in addition, they affect the tumour microenvironment to enhance anti-tumour immunity. We demonstrate here another reason to explain their efficacy. Tumour cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing exit from G1 or by inducing replication stress and genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize cells to CDK4/6 inhibition. Together, this demonstrates how oncogenic signals that have evolved to stimulate constitutive tumour growth and proliferation can be driven to cause toxic cell growth and irreversible cell cycle exit when proliferation is halted in G1.

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Section: Discussionmentioning

confidence: 99%

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Foy

Crozier

Pareri

et al. 2022

Preprint

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“…A recent report by Dang et al. demonstrated that Rb is degraded in G1 and that this process is blocked following its phosphorylation by cdk4/6 ( 14 ). Consequently, the authors demonstrated that treatment of breast cancer cells with cdk4/6 inhibitors promoted the degradation of Rb.…”

Section: Discussionmentioning

confidence: 99%

“…A number of hypotheses have been put forward to explain the development of cdk4/6 inhibitor resistance ( 1 , 12 ). A recent study demonstrated that prolonged treatment of breast cancer cells with these inhibitors resulted in the degradation of Rb and the transcriptional activation of the cdk6 gene ( 14 ). Taken together, these events promote resistance to cdk4/6 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The SREBP-dependent regulation of cyclin D1 coordinates cell proliferation and lipid synthesis

2022

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The sterol regulatory-element binding protein (SREBP) family of transcription factors regulates cholesterol, fatty acid, and triglyceride synthesis and metabolism. However, they are also targeted by the ubiquitin ligase Fbw7, a major tumor suppressor, suggesting that they could regulate cell growth. Indeed, enhanced lipid synthesis is a hallmark of many human tumors. Thus, the SREBP pathway has recently emerged as a potential target for cancer therapy. We have previously demonstrated that one of these transcription factors, SREBP1, is stabilized and remains associated with target promoters during mitosis, suggesting that the expression of these target genes could be important as cells enter G1 and transcription is restored. Activation of cyclin D-cdk4/6 complexes is critical for the phosphorylation and inactivation of the retinoblastoma protein (Rb) family of transcriptional repressors and progression through the G1 phase of the cell cycle. Importantly, the cyclin D-cdk4/6-Rb regulatory axis is frequently dysregulated in human cancer. In the current manuscript, we demonstrate that SREBP1 activates the expression of cyclin D1, a coactivator of cdk4 and cdk6, by binding to an E-box in the cyclin D1 promoter. Consequently, inactivation of SREBP1 in human liver and breast cancer cell lines reduces the expression of cyclin D1 and attenuates Rb phosphorylation. Rb phosphorylation in these cells can be rescued by restoring cyclin D1 expression. On the other hand, expression of active SREBP1 induced the expression of cyclin D1 and increased the phosphorylation of Rb in a manner dependent on cyclin D1 and cdk4/6 activity. Inactivation of SREBP1 resulted in reduced expression of cyclin D1, attenuated phosphorylation of Rb, and reduced proliferation. Inactivation of SREBP1 also reduced the insulin-dependent regulation of the cyclin D1 gene. At the same time, SREBP1 is known to play an important role in supporting lipid synthesis in cancer cells. Thus, we propose that the SREBP1-dependent regulation of cyclin D1 coordinates cell proliferation with the enhanced lipid synthesis required to support cell growth.

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“…Agents that block PI3K signaling are of particular interest as the latter is activated in greater than 70% of breast cancers [ 157 ]. Pre-clinical studies using TNBC patient derived xenograft and immunocompetent syngeneic animal models have shown that combining CDK4/6 inhibitors with those that block CK1ε [ 158 ] as well PI3Kα [ 159 ] resulted cell cycle arrest, apoptosis, the activation of tumor infiltrating T-cells and an increase tumor immunogenicity. Short-term inhibition of CDK4/6 has also been shown to sensitize ER+ breast cancers to radiation therapy in pre-clinical models [ 160 ], highlighting an additional use for these agents in combination therapy.…”

Section: Targeting Cdk4 For Cancer Therapymentioning

confidence: 99%

CDK4: a master regulator of the cell cycle and its role in cancer

et al. 2022

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The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G 1 phase when the cell prepares to initiate DNA synthesis. Although Cdk 4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development and tumorigenesis as well as the current status and utility of approved small molecule CDK4/6 inhibitors that are currently being used as cancer therapeutics.

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Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Cited by 25 publications

References 39 publications

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

The SREBP-dependent regulation of cyclin D1 coordinates cell proliferation and lipid synthesis

CDK4: a master regulator of the cell cycle and its role in cancer

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