Ribociclib for HR-Positive, Advanced Breast Cancer

Araki, Kazuhiro; Miyoshi, Yasuo

doi:10.1056/nejmc1615255

Cited by 10 publications

(2 citation statements)

References 7 publications

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“…In fact, in the MONALEESA-2 study, one sudden death of a patient who had taken a prohibited concomitant medication with a known risk for QT prolongation (methadone) while being on ribociclib in association with grade 3 hypokalemia and a grade 2 prolongation in the QTcF interval has been reported [17]. …”

Section: Drug Interactions With Cdk4/6 Inhibitorsmentioning

confidence: 99%

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors

Ettl¹

2019

Breast Care

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Cyclin-dependent kinase (CDK) 4/6 inhibitors have become standard of care in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. They have been shown to double the efficacy of endocrine-based treatment. Three oral agents are available to date: palbociclib, ribociclib, and abemaciclib. The aim of this article is to give a short overview of the existing efficacy data, to summarize the recommended clinical monitoring procedures for patients under CDK4/6 inhibitors, and to shed light on the clinical management of the most common treatment-emergent adverse events. The hematological class side effect neutropenia as well as non-hematological toxicities (e.g., impaired liver function, prolonged QTc interval, and diarrhea) are discussed. In addition, the current knowledge about relevant drug interactions is reviewed.

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Section: Drug Interactions With Cdk4/6 Inhibitorsmentioning

confidence: 99%

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors

Ettl¹

2019

Breast Care

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“…Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers, both as single and combination therapies with traditional cytotoxic or molecular targeting agents. Currently, the most promising cell cycle inhibitors in anticancer therapeutics are orally bioavailable CDK4/6 inhibitors, which have received regulatory approval in combination with hormonal therapy for treatment of patients with metastatic hormone receptor (HR)-positive, Her2-negative breast cancer [25][26][27][28][29]. Many other compounds designed to interrupt cell cycle progression or checkpoint control have problems in demonstrating sufficient antitumor efficacy.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer

Lee

et al. 2020

Cancers

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Despite recent innovations and advances in early diagnosis, the prognosis of advanced gastric cancer remains poor due to a limited number of available therapeutics. Here, we employed pharmacogenomic analysis of 37 gastric cancer cell lines and 1345 small-molecule pharmacological compounds to investigate biomarkers predictive of cytotoxicity among gastric cancer cells to the tested drugs. We discovered that expression of CCNA2, encoding cyclin A2, was commonly associated with responses to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib). We also found that elevated CCNA2 expression is required to confer sensitivity to PLK1 inhibitors through increased mitotic catastrophe and apoptosis. Further, we demonstrated that CCNA2 expression is elevated in KRAS mutant gastric cancer cell lines and primary tumors, resulting in an increased sensitivity to PLK1 inhibitors. Our study suggests that CCNA2 is a novel biomarker predictive of sensitivity to PLK1 inhibitors for the treatment of advanced gastric cancer, particularly cases carrying KRAS mutation.

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Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

et al. 2021

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Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding, and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit, and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates, and comparative specialization toward its primary substrate Retinoblastoma (RB).

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Ribociclib for HR-Positive, Advanced Breast Cancer

Cited by 10 publications

References 7 publications

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors

Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer

Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

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