Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

Piemonte, Katrina M.; Webb, Bryan M.; Bobbitt, Jessica R.; Majmudar, Parth R.; Cuellar-Vite, Leslie; Bryson, Benjamin L.; Latina, Nicholas C.; Seachrist, Darcie D.; Keri, Ruth A.

doi:10.1016/j.jbc.2023.104834

Cited by 4 publications

(1 citation statement)

References 103 publications

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“…TNBC was shown to be highly sensitive to chemical inhibition of CDK7 activity via treatment with the inhibitors THZ1 and its derivative THZ2, which significantly display growth inhibitory effects in both TNBC cell lines and xenograft models [100]. Sensitivity to these inhibitors was correlated to a transcriptional addiction of TNBC to CDK7, whose activity ensures proper expression of genes essential for TNBC tumorigenicity [100], including condensin genes guaranteeing chromosome stability [101]. Coherent with CDK7's essential role for TNBC cell survival, high expression levels of this kinase are a marker of poor prognosis for TNBC patients [102].…”

Section: Cdk7 and Cdk12 Inhibitorsmentioning

confidence: 99%

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

Masci,

Naro,

Puxeddu

et al. 2023

Molecules

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Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors.

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Section: Cdk7 and Cdk12 Inhibitorsmentioning

confidence: 99%

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

Masci,

Naro,

Puxeddu

et al. 2023

Molecules

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Perspectives and mechanisms for targeting mitotic catastrophe in cancer treatment

Bai,

Zhou,

Peng

et al. 2023

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The two sides of chromosomal instability: drivers and brakes in cancer

Hosea,

Hillary,

Naqvi

et al. 2024

Sig Transduct Target Ther

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Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the “just-right” model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

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Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

Cited by 4 publications

References 103 publications

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

Perspectives and mechanisms for targeting mitotic catastrophe in cancer treatment

The two sides of chromosomal instability: drivers and brakes in cancer

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