Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice

Trakala, Marianna; Partida, David; Salazar, María; Maroto, María; Wachowicz, Paulina; Cárcer, Guillermo de; Malumbres, Marcos

doi:10.1182/blood-2015-03-634402

Cited by 18 publications

(19 citation statements)

References 44 publications

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“…SAC activation in Plk1 -/megakaryocytes resulted in prolonged mitotic arrest and induction of cell death, leading to severe thrombocytopenia in vivo. 76 These results are consistent with the adverse hematological effects reported in clinical trials with volasertib. Furthermore, it was demonstrated that Plk1 -/mice were embryonic lethal, suggesting a critical role for Plk1 in accurate cell cycle progression.…”

Section: B In Vivo Studies On Volasertib Monotherapysupporting

confidence: 86%

“…reported that Plk1 deficiency prevented megakaryocyte polyploidization, an essential step in the megakaryocyte maturation process and the formation of platelets. SAC activation in Plk1 ‐/‐ megakaryocytes resulted in prolonged mitotic arrest and induction of cell death, leading to severe thrombocytopenia in vivo . These results are consistent with the adverse hematological effects reported in clinical trials with volasertib.…”

Section: Volasertib Monotherapysupporting

confidence: 86%

“…Despite the observation that BI6727 was well tolerated in mice, as neither body weight loss nor adverse signs were observed, recent studies investigating the physiological function of Plk1 in vivo demonstrated some worrisome effects after Plk1 depletion. Trakala et al 76 reported that Plk1 deficiency prevented megakaryocyte polyploidization, an essential step in the megakaryocyte maturation process and the formation of platelets. SAC activation in Plk1 -/megakaryocytes resulted in prolonged mitotic arrest and induction of cell death, leading to severe thrombocytopenia in vivo.…”

Section: B In Vivo Studies On Volasertib Monotherapymentioning

confidence: 99%

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Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

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Section: B In Vivo Studies On Volasertib Monotherapysupporting

confidence: 86%

Section: Volasertib Monotherapysupporting

confidence: 86%

Section: B In Vivo Studies On Volasertib Monotherapymentioning

confidence: 99%

See 1 more Smart Citation

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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“…Therefore, any treatment that can reactivate the spindle checkpoint in cells under mitotic stress would be beneficial in overcoming resistance against any given therapy. Although PLK1 inhibition has previously been demonstrated to cause SAC activation in a limited number of studies [67,68], it has never been proposed as a way of overcoming resistance against anti-mitotic agents. Prolonged mitosis upon SAC activation is known to cause apoptotic cell death, although the exact mechanisms have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer

et al. 2018

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Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available.

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“…Secondary antibodies were Alexa fluorophore labeled goat/donkey IgG (1:250, Invitrogen). We used primary antibodies against: FLAG (Sigma F7425), Plk1 (1:2, Ref 79. ), Plk1-phospho-T210 (1:200, Abcam ab39068), Pericentrin (1:3000, Abcam ab4448), g-Tubulin (1:1000, Sigma T6557), Aurora B-phospho-T232 (Rockland 600-401-677), RacGAP1-phospho-Ser170 (Active Motif 39265-66), Sgo1 (1:100, S. Taylor, University of Manchester, England, UK), α tubulin (1:500, Sigma T6199) and α-tubulin-FITC conjugate (1:500, Sigma F2168).…”

mentioning

confidence: 99%

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

Cárcer

Venkateswaran

Salgueiro

et al. 2018

Preprint

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Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by Kras G12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.

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Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice

Abstract: Key Points Plk1 ablation activates an endomitotic checkpoint in megakaryocytes. Plk1 deficiency in megakaryocytes results in thrombocytopenia.

Cited by 18 publications

References 44 publications

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

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