bims-cyhorp 2022-06-12 papers

Issue of 2022–06–12
five papers selected by
Piotr Okupski,

Mini Rev Med Chem. 2022 Jun 06.

Cyclin-Dependent Kinase 4/6 Inhibitors Against Breast Cancer.

Mohammed Al-Kassim Hassan, Zeynep Ates-Alagoz.

Breast cancer is the most frequently diagnosed and leading cause of cancer-related deaths in women worldwide. Based on global cancer (GLOBOCAN) 2020 statistics, 1 in 4 cancer cases and 1 in 6 cancer deaths are attributable to breast cancer, leading both in incidence and mortality. To address the increasing burden of cancer, novel therapeutic approaches that target key hallmarks of cancer are explored in cancer drug discovery. Cyclin-dependent kinase (CDK) inhibitors are generally purine and pyrimidine analogues validated for the treatment of cancer due to their unique roles in cancer deregulation and novel therapeutic potentials. So far, three orally administered, potent and highly selective CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have been approved by the FDA for the targeted treatment of advanced or metastatic breast cancer in combination with endocrine therapy. Furthermore, several compounds derived from various synthetic scaffolds are being explored with promising results and positive outcomes in various stages of clinical trials. In this review, we highlight these CDK4/6 inhibitor compounds with potent anti-CDK4/6, in vitro and in vivo activities on breast cancer cells. With the remarkable prospects of these compounds, there is great optimism further novel CDK inhibitor compounds will be discovered in the future that could boost therapeutic options for cancer treatment.

Keywords: CDK4/6; Cyclin-dependent kinase inhibitors; breast cancer.; cell cycle; cyclin-D; synthetic scaffolds

DOI: https://doi.org/10.2174/1389557522666220606095540

JCO Precis Oncol. 2022 Jun;6 e2100473

Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice.

Tam Binh V Bui, Boudewijn M T Burgering, Andrei Goga, Hope S Rugo, Laura J van 't Veer.

PURPOSE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as effective treatments for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (mBC). Dedicated research efforts have been undertaken to find predictive biomarkers of response or resistance to these therapies although no molecular biomarkers for mBC have reached the clinic so far. This review aims to summarize and evaluate the performance of biomarkers in predicting progression-free survival in phase II and III clinical trials of CDK4/6 inhibitors in HR+/HER2- mBC.
METHODS: For this narrative review, a structured literature search of PubMed, Embase, and the Cochrane library (CENTRAL) was performed. Phase II or III clinical trials of a CDK4/6 inhibitor in patients with HR+/HER2- mBC reporting on at least one molecular biomarker analysis of progression-free survival were included. Publications and selected conference abstracts were included up until November 2021.
RESULTS: Twenty-two articles reporting biomarker results of 12 clinical trials were included. Retinoblastoma protein status and cyclin E1 mRNA expression were promising baseline biomarkers, whereas PIK3CA circulating tumor DNA ratio on treatment relative to baseline, change in plasma thymidine kinase activity, and circulating tumor cell count were potential dynamic biomarkers of response. A number of biomarkers were unsuccessful, despite a strong mechanistic rationale, and others are still being explored.
CONCLUSION: Our review of clinical trials showed that there are a number of promising biomarkers at baseline and several dynamic biomarkers that might predict response to CDK4/6 inhibitors. Validation of these findings and assessment of clinical utility are crucial to make the final translation to clinical practice. Better understanding of disease heterogeneity and further elucidation of resistance mechanisms could inform future studies of rationally selected biomarkers.

DOI: https://doi.org/10.1200/PO.21.00473

Oncologist. 2022 Jun 06. pii: oyac089. [Epub ahead of print]

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

Erik S Knudsen, Emily Schultz, Deanna Hamilton, Kris Attwood, Stephen Edge, Tracey O'Connor, Ellis Levine, Agnieszka K Witkiewicz.

BACKGROUND: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-).
PATIENTS AND METHODS: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies.
RESULTS: In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002).
CONCLUSIONS: The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

DOI: https://doi.org/10.1093/oncolo/oyac089

Cancers (Basel). 2022 May 30. pii: 2709. [Epub ahead of print]14(11):

The Emerging Role of Cyclin-Dependent Kinase Inhibitors in Treating Diet-Induced Obesity: New Opportunities for Breast and Ovarian Cancers?

Reyes Benot-Dominguez, Annamaria Cimini, Daniela Barone, Antonio Giordano, Francesca Pentimalli.

Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO). Here we provide an overview of the most recent studies involving nutraceuticals and other dietary strategies affecting cell-cycle pathways, which might impact the management of breast and ovarian cancers, as well as the repurposing of already commercialized chemotherapeutic options to treat DIO.

Keywords: CDK inhibitors (CDKIs); CDK4/6; RB1; breast cancer; cell-cycle inhibitors; diet-induced obesity (DIO); ovarian cancer

DOI: https://doi.org/10.3390/cancers14112709

Nature. 2022 Jun 08.

Core control principles of the eukaryotic cell cycle.

Souradeep Basu, Jessica Greenwood, Andrew W Jones, Paul Nurse.

Cyclin-dependent kinases (CDKs) lie at the heart of eukaryotic cell cycle control, with different cyclin-CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs)1,2. However, the principles on which cyclin-CDK complexes organize the temporal order of cell cycle events are contentious3. One model proposes that S-CDKs and M-CDKs are functionally specialized, with substantially different substrate specificities to execute different cell cycle events4-6. A second model proposes that S-CDKs and M-CDKs are redundant with each other, with both acting as sources of overall CDK activity7,8. In this model, increasing CDK activity, rather than CDK substrate specificity, orders cell cycle events9,10. Here we reconcile these two views of core cell cycle control. Using phosphoproteomic assays of in vivo CDK activity in fission yeast, we find that S-CDK and M-CDK substrate specificities are remarkably similar, showing that S-CDKs and M-CDKs are not completely specialized for S phase and mitosis alone. Normally, S-CDK cannot drive mitosis but can do so when protein phosphatase 1 is removed from the centrosome. Thus, increasing S-CDK activity in vivo is sufficient to overcome substrate specificity differences between S-CDK and M-CDK, and allows S-CDK to carry out M-CDK function. Therefore, we unite the two opposing views of cell cycle control, showing that the core cell cycle engine is largely based on a quantitative increase in CDK activity through the cell cycle, combined with minor and surmountable qualitative differences in catalytic specialization of S-CDKs and M-CDKs.

DOI: https://doi.org/10.1038/s41586-022-04798-8