Sequential combination of bortezomib and WEE1 inhibitor, MK-1775, induced apoptosis in multiple myeloma cell lines

Barbosa, Rebecca S.S.; Dantonio, Paola M.; Guimaraes, T. Oliveira; Oliveira, Mariana Bleker de; Alves, Veruska Lia Fook; Sandes, Alex Freire; Fernando, Rodrigo Carlini; Colleoni, Gisele W. B.

doi:10.1016/j.bbrc.2019.08.163

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…Moreover, we demonstrated that ALL cells are dependent on WEE1 functionality for their survival and proliferation and that PKMYT1 levels may influence the sensitivity to the WEE1 inhibitor AZD-1775 [ 35 ]. Similar results on the role of WEE1 were obtained in multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocyte leukemia (CLL) [ 36 – 39 ]. In AML cells, WEE1 and PKMYT1 are key gene discriminating between FLT3 -ITD, FLT3 -TKD, and NRAS -mutated samples.…”

Section: Wee1 and Pkmyt1 Deregulation In Cancer Cellssupporting

confidence: 57%

“…Moreover, strong synergism has been observed by combining adavosertib with small molecules, including DDR-related inhibitors (CDK2 [ 89 ], CDK4-6 [ 149 ], CHK1 [ 103 , 140 – 142 ], ATM [ 132 – 135 ], AURORA A [ 147 ], PARP1 [ 144 ], SIRT1 [ 148 ] inhibitors), histone deacetylase (HDAC) inhibitors [ 41 , 130 , 131 ], tyrosine kinase inhibitors (BCR-ABL1 inhibitors [ 35 ]), anti-apoptotic protein inhibitors (BCL2 and MCL1 inhibitors [ 143 ]), mTOR inhibitor [ 136 – 139 ], and proteasome inhibitors [ 36 ].…”

Section: Development Of Wee1 and Pkmyt1 Inhibitorsmentioning

confidence: 99%

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A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

et al. 2020

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The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.

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Section: Wee1 and Pkmyt1 Deregulation In Cancer Cellssupporting

confidence: 57%

Section: Development Of Wee1 and Pkmyt1 Inhibitorsmentioning

confidence: 99%

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

et al. 2020

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“…Clinical studies that utilised MK1775 with other cancer‐preventing drugs have found favorable clinical outcome in combination with gemcitabine, cisplatin or carboplatin in patients with advanced solid tumours 43,49 . We also analysed the effect of MK1775 in combination therapy in vitro and observed synergistic anti‐MM activity of MK1775 with BTZ, which is in line with a previous study 50 . Moreover, the combination eliminates cancer stem‐like cell characteristics from the bulk cell population, though BTZ treatment alone produced a rise in CSC characteristics.…”

Section: Discussionsupporting

confidence: 85%

The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma

Liang

Wang

et al. 2020

Br J Haematol

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Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patientderived CD138 + plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138 + cells by decreasing ALDH1 + cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1 + cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.

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“…These observations have supported the rationale for targeting WEE1 in combination with replicative stress-inducing agents in preclinical models that have shown encouraging efficacy [ 97 ]. Preclinical studies suggest, indeed, that WEE inhibitors have single agent and chemo-sensitizer effects also in MM [ 111 , 112 , 113 , 114 ].…”

Section: Harnessing Replicative Stress As a Cancer Vulnerability In MMmentioning

confidence: 99%

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Botrugno

Tonon

2021

Cancers

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Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

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Sequential combination of bortezomib and WEE1 inhibitor, MK-1775, induced apoptosis in multiple myeloma cell lines

Cited by 16 publications

References 38 publications

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

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