bims-cyhorp 2023-01-08 papers

Issue of 2023–01–08
five papers selected by
Piotr Okupski,

J Pharm Biomed Anal. 2022 Dec 20. pii: S0731-7085(22)00632-X. [Epub ahead of print]225 115211

Therapeutic drug monitoring in breast cancer therapy - LC-MS/MS method for quantification of the CDK4/6 inhibitors abemaciclib, palbociclib, ribociclib, and major metabolites abemaciclib M20 and M2 in human serum.

Katharina Habler, Anne-Sophie Kalla, Michael Rychlik, Michael Vogeser, Daniel Teupser.

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib were approved by the U.S. Food and Drug Administration (FDA) and European Medicine Agency for the treatment of breast cancer between 2015 and 2018. Oral tumor therapeutics extend the options for cancer therapy, but also challenge physicians and patients. The aim of the present work was to establish a semi-automated liquid-chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of abemaciclib, its active metabolites abemaciclib M20 and M2, palbociclib, and ribociclib in human serum. Detuning of ribociclib enabled the development of a simultaneous quantification method for abemaciclib, M20, M2, palbociclib, and ribociclib in the respective relevant concentration ranges based on semi-automated sample preparation with isotope dilution LC-MS/MS. The method was validated according to the guidance of the FDA. The LC-MS/MS method was successfully validated according to FDA and showed inaccuracies ≤ 10.7% and imprecisions ≤ 8.51%. Linearity was given from 20 to 800 ng/mL for abemaciclib, 15-600 ng/mL for M20, 10-400 ng/mL for M2 and palbociclib, and 100-4000 ng/mL for ribociclib. Normalized matrix factors and process efficiency showed no significant matrix effects regardless of the analytes. To demonstrate the applicability of the method, authentic samples were also analyzed. This novel semi-automated LC-MS/MS method covering all previously approved CDK4/6 inhibitors as well as the similarly pharmacologically active metabolites in human serum simultaneously was developed for potential future use in routine analysis in order to improve personalized therapy, patient safety, and treatment success.

Keywords: Abemaciclib; CDK4/6 inhibitor; LCMS/; MS; Palbociclib; Ribociclib; Therapeutic drug monitoring

DOI: https://doi.org/10.1016/j.jpba.2022.115211

Medicine (Baltimore). 2022 Dec 23. 101(51): e32238

Facing the CDK4/6i resistance dilemma in patients with breast cancer, exploration of the resistance mechanism and possible reverse strategy: A narrative review.

Jiayi Wu, Wei Wang, Xiying Shao, Guang Lin, Xiaojia Wang.

Breast cancer is one of the highest rates of malignancy of women, approximate 70% metastatic breast cancer are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-). Hormone therapy is the primary strategy of HR+/HER2- metastatic breast cancer. With the permission of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), progress free survival and overall survival were significantly licensed. However, inevitable outcome of CDK4/6i resistance has become the main reason that restricts the clinical benefit of patients. In recent years, the research on dealing with drug resistance has become a hot topic, a large number of molecular mechanisms have been focused, and a lot of experiments have been carried out at the preclinical level. This review summarizes the current knowledge of CDK4/6i resistance mechanism, systematically expounds the signaling pathways and targets leading to CDK4/6i resistance, analyzes different ways and mechanisms, and provides theoretical guidance for the clinical reversal of endocrine therapy resistance.

DOI: https://doi.org/10.1097/MD.0000000000032238

Naunyn Schmiedebergs Arch Pharmacol. 2023 Jan 04.

Novel combination treatment of CDK 4/6 inhibitors with PARP inhibitors in triple negative breast cancer cells.

Gamze Guney Eskiler, Zeynep Ozman, Ayten Haciefendi, Demet Cansaran-Duman.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors provide promising results for treating hormone receptor-positive breast cancer. However, the efficacy of CDK4/6 inhibitors remains uncertain in triple negative breast cancer (TNBC) patients with particularly carrying RB-deficient tumors. Poly-(ADP-ribose) polymerase (PARP) inhibitors offer a therapeutic strategy for the treatment of BRCA-mutated TNBC patients. However, the acquired drug resistance, changes in the cell cycle regulation, and DNA damage repair have demonstrated the necessity for developing new combination strategies. This preclinical study assessed a combinatory treatment of the CDK4/6 inhibitor abemaciclib with PARP inhibitors talazoparib (TAL) in HCC1937 BRCA-mutated RB-deficient TNBC cells and TAL-resistant HCC1937-R cells through WST-1 analysis, annexin V, cell cycle, acridine orange/propidium iodide staining, RT-PCR, and apoptosis array. Our findings revealed that abemaciclib and TAL combination synergistically suppressed the growth of TNBC cells and overcame TAL resistance through G0/G1 arrest and the activity of both intrinsic and extrinsic apoptotic pathways. These preliminary results suggest that the combination of abemaciclib and TAL could expand the use of these inhibitors in BRCA mutated and RB deficient TNBC patients and potentially overcomes PARP inhibitors resistance.

Keywords: Abemaciclib; Apoptosis; Resistance; Talazoparib; Triple-negative breast cancer

DOI: https://doi.org/10.1007/s00210-022-02375-4

Front Oncol. 2022 ;12 1026434

Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report.

Poumeaud François, Fontanier Anna, Dion Jérémie, Mathevet Quentin, Cointault Olivier, Uro-Coste Emmanuelle, Marty Céline, Dalenc Florence, Girardie Pierre, Rataboul Anaïs.

We report the fourth described case of severe toxic rhabdomyolysis occurring in an 81-year-old woman caused by the concomitant administration of palbociclib taken at the usual dosage (125 mg per day) and simvastatin. To the best of our knowledge, this is the first reported case successfully treated by plasma exchanges, with complete functional recovery within two months. The severity of this case justifies further consideration of pharmacokinetic interactions between palbociclib or other CDK-4-6 inhibitors and statins, which potentially increase the risk of an adverse event.

Keywords: interaction; myositis; palbociclib; plasmatic exchange; rhabdomyolysis; simvastatin

DOI: https://doi.org/10.3389/fonc.2022.1026434

Bratisl Lek Listy. 2023 Jan 04.

The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors.

Mark Hives, Jana Jurecekova, Klaudia Hives Holeckova, Jan Kliment, Monika Kmetova Sivonova.

The cell cycle covers cell proliferation and growth and is strictly regulated by cyclin-dependent kinase, cyclins and their inhibitors. Cyclin-dependent kinases are serine/threonine kinases that are activated in certain phases of the cell cycle by regulatory subunits, cyclins, with which they form functional heterodimeric complexes. Under physiological conditions, the activation of cyclin-dependent kinases and cyclins is strictly controlled. The formation of these complexes is inhibited, as needed, either specifically or non-specifically, by cyclin-dependent kinase inhibitors. Progression through the cell cycle is a critical process that drives many aspects of cellular function. The cell cycle is a series of events that occurs in a repeating pattern. Each cell cycle consists of two phases, interphase and mitotic phase. Their dysregulation leads to disruption of cell cycle coordination and uncontrollable cell proliferation, which is the main feature of tumorigenesis (Fig. 1, Ref. 69). Keywords: cell cycle, regulation, cyclin‑dependent kinases, cyclins, inhibitors.

DOI: https://doi.org/10.4149/BLL_2023_039