CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities

Knudsen, Erik S.; Kumarasamy, Vishnu; Nambiar, Ram; Pearson, Joel D.; Vail, Paris; Rosenheck, Hanna R.; Wang, Jianxin; Eng, Kevin; Bremner, Rod; Schramek, Daniel; Rubin, Seth M.; Welm, Alana L.; Witkiewicz, Agnieszka K.

doi:10.1016/j.celrep.2022.110448

Cited by 63 publications

(55 citation statements)

References 75 publications

(93 reference statements)

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“…CDKs are serine/threonine kinases that play a role in eukaryotic cell cycle progression and transcription [ 18 ]. Additionally, recent studies reveal high heterogeneity of CDKs in primary and metastatic tumors, indicating role in cancer metastasis [ 52 – 54 ]. CDKs are becoming appealing and potent targets for anti-cancer therapeutics because of their functional relevance [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

et al. 2022

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Cell cycle dysregulation is a characteristic hallmark of malignancies, which results in uncontrolled cell proliferation and eventual tumor formation. Cyclin-dependent kinase 1 (CDK1) is a member of the family of cell cycle regulatory proteins involved in cell cycle maintenance. Given that overexpression of CDK1 has been associated with cancer, CDK1 inhibitors may restore equilibrium to the skewed cell cycle system and operate as an effective therapeutic drug. This study aimed to identify and classify inhibitors having a higher affinity for CDK1 and also evaluate the expression pattern and prognostic relevance of CDK1 in a wide range of cancers. We investigated therapeutic molecules structurally similar to dinaciclib for their ability to inhibit CDK1 selectively. To assess the therapeutic potential of screened Dinaciclib analogs, we used drug likeliness analysis, molecular docking, and simulation analysis. CDK1 was found to be highly upregulated across several malignancies and is associated with poor overall and relapse-free survival. Molecular docking and dynamics evaluation identified two novel dinaciclib analogs as potent CDK1 inhibitors with high binding affinity and stability compared to dinaciclib. The results indicate that increased CDK1 expression is associated with decreased OS and RFS. Additionally, dinaciclib analogs are prospective replacements for dinaciclib since they exhibit increased binding affinity, consistent with MDS findings, and have acceptable ADMET qualities. The discovery of new compounds may pave the road for their future application in cancer prevention through basic, preclinical, and clinical research. Supplementary Information The online version contains supplementary material available at 10.1007/s12032-022-01748-2.

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Section: Discussionmentioning

confidence: 99%

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

et al. 2022

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“…Our results thus suggest that in cells with wild-type CDKN2A, the insensitivity to CDK4 inhibition could be directly due to the absence of the main target of CDK4/6i, i.e. active phosphorylated CDK4, rather than to the two generally considered mechanisms -absence/mutation of pRb, or amplified cyclin E1-mediated activation of CDK2 (33,58,(81)(82)(83). It remains difficult to understand why the deficiency of pRb is sufficient to generate the observed insensitivity to CDK4/6i in the presence of the other proteins of the RB family, p107 (RBL1) and p130 (RB2), which are also inactivated by CDK4 phosphorylation and capable of blocking the cell cycle (34,35,37,38,84,85).…”

Section: Discussionmentioning

confidence: 79%

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition

Paternot

Raspé

Meiller

et al. 2022

Preprint

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.

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“…Identifying the governing factors that organize the cell duration heterogeneities is a challenging task (8,9,12,17,(19)(20)(21)(22). In this article, we combined live-cell imaging studies of FUCCI-HeLa cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Cell cycle period and phase durations of mammalian cells demonstrate a high degree of heterogeneity under culture conditions (1–9), and within a tumor micro-environment (10, 11). Often, such heterogeneities significantly influence the cell-fate decision-making (12–16).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional fluctuations govern the serum dependent cell cycle duration heterogeneities in Mammalian cells

Govindaraj

Sarma

Karulkar

et al. 2022

Preprint

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Mammalian cells exhibit a high degree of intercellular variability in cell cycle period and phase durations. However, the factors orchestrating the cell cycle duration heterogeneities remain unclear. Herein, by combining cell cycle network-based mathematical models with live single-cell imaging studies under varied serum conditions, we demonstrate that fluctuating transcription rates of cell cycle regulatory genes across cell lineages and during cell cycle progression in mammalian cells majorly govern the robust correlation patterns of cell cycle period and phase durations among sister, cousin, and mother-daughter lineage pairs. However, for the overall cellular population, alteration in serum level modulates the fluctuation and correlation patterns of cell cycle period and phase durations in a correlated manner. These heterogeneities at the population level can be fine-tuned under limited serum conditions by perturbing the cell cycle network using a p38-signaling inhibitor without affecting the robust lineage level correlations. Overall, our approach identifies transcriptional fluctuations as the key controlling factor for the cell cycle duration heterogeneities, and predicts ways to reduce cell-to-cell variabilities by perturbing the cell cycle network regulations.

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CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities

Cited by 63 publications

References 75 publications

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition

Transcriptional fluctuations govern the serum dependent cell cycle duration heterogeneities in Mammalian cells

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