bims-cyhorp 2021-09-26 papers

Issue of 2021–09–26
five papers selected by
Piotr Okupski,

Clin Breast Cancer. 2021 Aug 14. pii: S1526-8209(21)00239-1. [Epub ahead of print]

Endocrine Therapy With or Without CDK4/6 Inhibitors in Women With Hormone-receptor Positive Breast Cancer: What do we Know About the Effects on Cognition?

Philippe R Lee Meeuw Kjoe, Elsken van der Wall, Sanne B Schagen.

Adjuvant endocrine therapy (ET) is the cornerstone of treatment for hormone-receptor positive breast cancer. Recently, ET is increasingly combined with "cyclin-dependent kinases 4 and 6'' (CDK4/6) inhibitors. Given the importance of estrogens in neural processes and the role of cyclin D in hippocampal cell proliferation, it is plausible that these therapies affect cognition, but studies on these potential cognitive effects are sparse. In this review, we summarize existing knowledge on the cognitive effects of ET and CDK4/6 inhibitors in pre-, peri- and postmenopausal patients with breast cancer. We show that several clinical studies support adverse cognitive effects, especially on verbal memory, after ET-induced decrease of estrogen-levels or inactivation of estrogen-receptors. Clinical studies on the cognitive effects of CDK4/6 inhibitors are virtually non-existent and no conclusions can yet be drawn. Longitudinal studies on the cognitive effects of the combined ET-CDK4/6 inhibitors are highly needed to properly inform patients about potential short-term and long-term cognitive side effects. These studies should preferably include cognitive assessments (including a measurement prior to ET), and be designed in such a way that they can account for variables such as type and duration of ET, CDK4/6 inhibition, menopausal status, and other disease- and treatment-related symptoms that can impact cognition, such as fatigue and distress.

Keywords: Metastatic; Tamoxifenaromatase inhibitorsestrogensquality of life

DOI: https://doi.org/10.1016/j.clbc.2021.08.002

Cancer Discov. 2021 Sep 20. pii: candisc.1726.2020. [Epub ahead of print]

INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors.

Cyclin-dependent kinases 4 and 6 (CDK4/6), represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identify several genetic alterations (e.g. FAT1, PTEN or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g. p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C/D-cyclin/CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-20-1726

Int J Dev Biol. 2021 ;65(7-8-9): 487-496

Mitotic timing is differentially controlled by A- and B-type cyclins and by CDC6 associated with a bona fide CDK inhibitor Xic1 in Xenopus laevis cell-free extract.

Mohammed El Dika, Lisa Wechselberger, Bilal Djeghout, Djamel Eddine Benouareth, Krystyna Jęderka, Sławomir Lewicki, Robert Zdanowski, Claude Prigent, Malgorzata Kloc, Jacek Z Kubiak.

The timing of the M-phase is precisely controlled by a CDC6-dependent mechanism inhibiting the mitotic histone H1 kinase. Here, we describe the differential regulation of the dynamics of this mitotic kinase activity by exogenous cyclin A or cyclin B in the Xenopus laevis cycling extracts. We show that the experimental increase in cyclin A modifies only the level of histone H1 kinase activity, while the cyclin B increase modifies two parameters: histone H1 kinase activity and the timing of its full activation, which is accelerated. On the other hand, the cyclin A depletion significantly delays full activation of histone H1 kinase. However, when CDC6 is added to such an extract, it inhibits cyclin B-associated histone H1 kinase, but does not modify the mitotic timing in the absence of cyclin A. Further, we show via p9 co-precipitation with Cyclin-Dependent Kinases (CDKs), that both CDC6 and the bona fide CDK1 inhibitor Xic1 associate with the mitotic CDKs. Finally, we show that the Xic1 temporarily separates from the mitotic CDKs complexes during the peak of histone H1 kinase activity. These data show the differential coordination of the M-phase progression by cyclin A- and cyclin B-dependent CDKs, confirm the critical role of the CDC6-dependent histone H1 kinase inhibition in this process, and show that CDC6 acts differentially through the cyclin B- and cyclin A-associated CDKs. This CDC6- and cyclins-dependent mechanism likely depends on the precisely regulated association of Xic1 with the mitotic CDKs complexes. We postulate that: i. the dissociation of Xic1 from the CDKs complexes allows the maximal activation of CDK1 during the M-phase, ii. the switch between cyclin A- and cyclin B-CDK inhibition upon M-phase initiation may be responsible for the diauxic growth of mitotic histone H1 kinase activity.

DOI: https://doi.org/10.1387/ijdb.200313jk

J Clin Pharmacol. 2021 Sep 23.

Pharmacodynamic Modeling of CDK4/6 Inhibition Related Biomarkers and the Characterization of the Relationship between Biomarker Response and Progression Free Survival in Patients with Advanced Breast Cancer.

Yanke Yu, Wan Sun, Yuan Liu, Diane Wang.

Identification of a pharmacodynamic (PD) biomarker which is predictive of the efficacy outcome is of ultimate interest in drug development. The objectives of the current analyses are to develop the PKPD model for biomarkers (thymidine kinase 1 (TK1) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues) related to CDK4/6 inhibition by palbociclib and to explore the relationship of the biomarker response with the efficacy endpoint (PFS). The data used for analysis consisted of extensive sampling of palbociclib PK and longitudinal rich sampling for the PD biomarkers TK1, pRb, and Ki67 in 26 patients. A 2-compartment model was used to describe the PK of palbociclib. A precursor-dependent indirect response PD model was developed to describe the pRb time course, whereas, a similar PD model with an additional transit compartment to model the delayed effect on Ki67 and TK1 response was used to describe the Ki67 and TK1 time-course. Palbociclib effect on biomarkers was modeled as Imax inhibitory model. Cox proportional hazard model was used to assess the relationship of PFS with the biomarker response. The PK/PD models adequately described the observed PK of palbociclib and the longitudinal change of pRb, Ki67, and TK1. Palbociclib exposure significantly correlated with the reduction of all three biomarkers, and the estimated IC50 value were 45.2, 42.4, 50.2 ng/mL, respectively, for pRb, Ki67, and TK1. The exploratory biomarker-response analyses showed that a longer PFS was associated with lower baseline TK1 and simulated minimum TK1. Such results may warrant further confirmation from future large-scale study. Clinical Trial Registration: NCT02499146 This article is protected by copyright. All rights reserved.

Keywords: CDK4/6; PFS; Pharmacodynamics; modeling; thymidine kinase

DOI: https://doi.org/10.1002/jcph.1971

Bioorg Chem. 2021 Sep 11. pii: S0045-2068(21)00724-0. [Epub ahead of print]116 105347

Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).

Esraa Z Mohammed, Walaa R Mahmoud, Riham F George, Ghaneya S Hassan, Farghaly A Omar, Hanan H Georgey.

New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.

Keywords: Anti-proliferative; CDK inhibitors; Molecular docking; Pyrazole based derivatives

DOI: https://doi.org/10.1016/j.bioorg.2021.105347