bims-cyhorp 2021-10-03 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021‒10‒03
eleven papers selected by
Piotr Okupski

Association between cyclin-dependent kinase 4/6 inhibitors and venous thromboembolism: analysis of F.A.E.R.S. data.
An Overview of the Treatment Efficacy and Side Effect Profile of Pharmacological Therapies in Asian Patients with Breast Cancer.
High-throughput virtual screening followed by in vitro investigation to identify new lead inhibitors of Cyclin Dependent Kinase 4.
Real-world benefit of combination palbociclib and endocrine therapy for metastatic breast cancer and correlation with neutropenia.
Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.
Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma.
Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy.
Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma.
Targeting the CDK6 Dependence of Ph+ Acute Lymphoblastic Leukemia.
Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations.
Myocardial dysfunction caused by abemaciclib: a case report.

Expert Opin Drug Saf. 2021 Sep 28. 1-7

Association between cyclin-dependent kinase 4/6 inhibitors and venous thromboembolism: analysis of F.A.E.R.S. data.

Ming-Ming Yan, Shu-Shan Wu, Yu-Peng Qi, Zi-Ran Li, Qian Zhang, Hui Zhao, Ming-Kang Zhong, Xiao-Yan Qiu.

  Objectives:Real world studies have started to emerged on occurrence of venous thromboembolism (VTE) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but still deserve constant surveillance and evaluation. This study was to analyze this association. Methods: Adverse event cases were acquired from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database betweenJanuary 1st 2015 and December 31st 2020.Signals indicating association between CDK 4/6 inhibitors and VTE were identified by reporting odds ratio (ROR). Results: CDK 4/6 inhibitors had a total of 631 reports of VTE (ROR 1.44, 95% CI 1.33-1.55) compared with non-CDK 4/6 inhibitors. Palbociclib (ROR 1.42, 95% CI 1.09-1.88) demonstratedthe highest number of VTE reports, followed by ribociclib (ROR 1.41, 95% CI 1.29-1.54) and abemaciclib (ROR 0.92, 95% CI 0.72-1.17). Conclusions:Although it is not able to confirm the casual relationship between VTE and CDK4/6 inhibitors, this study suggested signal of VTE reporting in patients receiving CDK4/6 inhibitors, which is likely to reflect a potential association. The results may enhance physicians' awareness of the potential side effect of VTE associated with CDK 4/6 inhibitors. An early recognition of VTE signs/symptoms could decrease the morbidity and severity of such adverse events.

Keywords:  C.D.K. 4/6 inhibitors; drug safety; pharmacovigilance; reporting odds ratio; venous thromboembolism

DOI:  https://doi.org/10.1080/14740338.2021.1981856
Target Oncol. 2021 Sep 28.

An Overview of the Treatment Efficacy and Side Effect Profile of Pharmacological Therapies in Asian Patients with Breast Cancer.

Yen-Shen Lu, Winnie Yeo, Yoon-Sim Yap, Yeon Hee Park, Kenji Tamura, Huiping Li, Rebecca Cheng.

Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients.

DOI: https://doi.org/10.1007/s11523-021-00838-x
J Mol Graph Model. 2021 Sep 16. pii: S1093-3263(21)00191-1. [Epub ahead of print]109 108020

High-throughput virtual screening followed by in vitro investigation to identify new lead inhibitors of Cyclin Dependent Kinase 4.

V Divya, V L Pushpa.

  In the family of serine/threonine kinases, Cyclin Dependent Kinase 4 (CDK4), is an important regulator in numerous signal transduction pathways. The cell cycle is dysregulated in human breast adenocarcinoma (MCF-7). A set of various categorical QSAR models were generated and validated in the current examination. A recursive partition model, with predictive ability shown by an accuracy of greater than 0.90, was used for virtual screening of 500,000 molecules. Following a consecutive series of molecular docking procedures, followed by pharmacokinetic analysis of 49759 molecules predicted to have pIC50 greater than 7.39, 25 molecules displayed properties that could be described as drug-like. We selected the lead molecules in the MCF-7 cell line based on its ability to promote cell cycle progression.

Keywords:  Cyclin dependent Kinase-4; Molecular docking; QSAR; Virtual screening

DOI:  https://doi.org/10.1016/j.jmgm.2021.108020
Cancer Med. 2021 Sep 30.

Real-world benefit of combination palbociclib and endocrine therapy for metastatic breast cancer and correlation with neutropenia.

James Sun, Xiaojun Zhong, Junjie Ma, Weihong Sun, Hyo S Han, Hatem H Soliman, Loretta S Loftus, Ricardo L B Costa, Avan J Armaghani, Aixa E Soyano-Muller, Brian J Czerniecki, M Catherine Lee, John V Kiluk, Nazanin Khakpour, Susan J Hoover, Christine Laronga, Hung T Khong.

  BACKGROUND: Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression-free survival (PFS) in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real-world benefit of first-line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors.METHODS: This study included HR-positive, HER2-negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression-free survival (PFS) was determined using Kaplan-Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil-to-lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time-dependent variable.
RESULTS: In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93-NR). Median PFS for patients with bone-only metastases (n = 54) was not reached (95% CI 18.21-NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33-33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71-0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97-1.18, p = 0.203).
CONCLUSION: The effectiveness of palbociclib and endocrine therapy in the treatment of HR-positive, HER2-negative mBC in the real-world setting is similar to the efficacy reported in the PALOMA-2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Keywords:  absolute neutrophil count; endocrine therapy; metastatic breast cancer; neutropenia; neutrophil-lymphocyte ratio; palbociclib

DOI:  https://doi.org/10.1002/cam4.4295
Nat Cancer. 2021 Apr;2(4): 429-443

Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.

Xuewei Wu, Xiaobao Yang, Yan Xiong, Ruitong Li, Takahiro Ito, Tamer A Ahmed, Zoi Karoulia, Christos Adamopoulos, Hong Wang, Li Wang, Ling Xie, Jing Liu, Beatrix Ueberheide, Stuart A Aaronson, Xian Chen, Sean G Buchanan, William R Sellers, Jian Jin, Poulikos I Poulikakos.

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

DOI: https://doi.org/10.1038/s43018-021-00174-z
Ann Thorac Surg. 2021 Sep 27. pii: S0003-4975(21)01670-2. [Epub ahead of print]

Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma.

Hee-Jin Jang, Cynthia Y Truong, Eric M Lo, Hudson M Holmes, Daniela Ramos, Maheshwari Ramineni, Ju-Seog Lee, Daniel Y Wang, Massimo Pietropaolo, R Taylor Ripley, Bryan M Burt, Hyun-Sung Lee.

  BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (four responders and four non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.
RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(-/-) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone.
CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.

Keywords:  CDK4/6 inhibitor; CDKN2A; immune checkpoint inhibitors; mesothelioma; systems immunology

DOI:  https://doi.org/10.1016/j.athoracsur.2021.08.054
Acta Pharm Sin B. 2021 Sep;11(9): 2738-2748

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy.

Kailin Li, Jieqiong You, Qian Wu, Wen Meng, Qiaojun He, Bo Yang, Chengliang Zhu, Ji Cao.

  Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality. In this review, we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

Keywords:  Antitumor therapy; Cyclin-dependent kinase; MYC; Oncogenes; P53; PARP; RAS; Synthetic lethality

DOI:  https://doi.org/10.1016/j.apsb.2021.01.002
Br J Cancer. 2021 Sep 29.

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma.

Elisabet Aliagas, Ania Alay, Maria Martínez-Iniesta, Miguel Hernández-Madrigal, David Cordero, Mireia Gausachs, Eva Pros, Maria Saigí, Sara Busacca, Annabel J Sharkley, Alan Dawson, Ramón Palmero, José C Ruffinelli, Susana Padrones, Samantha Aso, Ignacio Escobar, Ricard Ramos, Roger Llatjós, August Vidal, Eduard Dorca, Mar Varela, Montse Sánchez-Céspedes, Dean Fennell, Cristina Muñoz-Pinedo, Alberto Villanueva, Xavi Solé, Ernest Nadal.

BACKGROUND: There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy.METHODS: We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM.
RESULTS: Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice.
CONCLUSIONS: Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

DOI: https://doi.org/10.1038/s41416-021-01547-y
Genes (Basel). 2021 Aug 29. pii: 1355. [Epub ahead of print]12(9):

Targeting the CDK6 Dependence of Ph+ Acute Lymphoblastic Leukemia.

Patrizia Porazzi, Marco De Dominici, Joseph Salvino, Bruno Calabretta.

  Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190- or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, TKIs have markedly improved the outcome of Ph+ ALL, in particular if this treatment is followed by bone marrow transplantation. However, resistance to TKIs develops with high frequency, causing leukemia relapse that results in <5-year overall survival. Thus, new therapies are needed to address relapsed/TKI-resistant Ph+ ALL. We have shown that expression of cell cycle regulatory kinase CDK6, but not of the highly related CDK4 kinase, is required for the proliferation and survival of Ph+ ALL cells. Comparison of leukemia suppression induced by treatment with the clinically-approved dual CDK4/6 inhibitor palbociclib versus CDK6 silencing revealed that the latter treatment was markedly more effective, probably reflecting inhibition of CDK6 kinase-independent effects. Thus, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs) that preferentially degrade CDK6 over CDK4. One compound termed PROTAC YX-2-107, which degrades CDK6 by recruiting the Cereblon ubiquitin ligase, markedly suppressed leukemia burden in mice injected with de novo or TKI-resistant Ph+ ALL. The effect of PROTAC YX-2-107 was comparable or superior to that of palbociclib. The development of CDK6-selective PROTACs represents an effective strategy to exploit the "CDK6 dependence" of Ph+ ALL cells while sparing a high proportion of normal hematopoietic progenitors that depend on both CDK6 and CDK6 for their survival. In combination with other agents, CDK6-selective PROTACs may be valuable components of chemotherapy-free protocols for the therapy of Ph+ ALL and other CDK6-dependent hematological malignancies.

Keywords:  apoptosis; cell cycle; chemotherapy; kinase; proteolysis-targeting chimeras (PROTACs)

DOI:  https://doi.org/10.3390/genes12091355
Biomedicines. 2021 Sep 10. pii: 1197. [Epub ahead of print]9(9):

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations.

Vikas Kumar, Shraddha Parate, Gunjan Thakur, Gihwan Lee, Hyeon-Su Ro, Yongseong Kim, Hong Ja Kim, Myeong Ok Kim, Keun Woo Lee.

  The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits-ZINC20392430, SN00112175, SN00004718, and SN00262261-having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies.

Keywords:  CDK7; MD simulation; MM-PBSA; cancer; molecular docking; pharmacokinetic properties; pharmacophore

DOI:  https://doi.org/10.3390/biomedicines9091197
Int Cancer Conf J. 2021 Oct;10(4): 324-328

Myocardial dysfunction caused by abemaciclib: a case report.

Takuya Oyakawa, Lina Inagaki, Zhensheng Hua, Aya Ebihara, Toshimi Takano, Shinji Ohno, Taro Shiga.

  A 68-year-old female patient with metastatic breast cancer presented 12 weeks after starting chemotherapy with abemaciclib and fulvestrant with breathlessness, peripheral edema, and weight gain. Brain natriuretic peptide (BNP) and troponin I levels were raised above normal, and chest radiography revealed an increase in the cardiothoracic ratio from 47% before chemotherapy to 55%. The transthoracic echocardiogram showed a reduction in left ventricular ejection fraction from 76% before chemotherapy to 68%. Contrast-enhanced cardiac magnetic resonance imaging (MRI) revealed delayed accumulation in the interventricular septum. Under the diagnosis of abemaciclib-induced myocardial dysfunction and heart failure, abemaciclib was discontinued, and enalapril and furosemide were started. Two months later, imaging revealed a cardiothoracic ratio of 47% with a left ventricular ejection fraction of 73%. A cardiac MRI after three months was normal. This case report demonstrates that cardiac dysfunction caused by abemaciclib is reversible if detected early and treated appropriately.

Keywords:  Abemaciclib; CDK4/6 inhibitor; Cardiac magnetic resonance imaging; Cardio-oncology; Heart failure; Myocardial dysfunction

DOI:  https://doi.org/10.1007/s13691-021-00500-3