bims-cyhorp 2021-09-12 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021–09–12
eight papers selected by
Piotr Okupski,

Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2.
Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.
Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib.
Docking to a Basic Helix Promotes Specific Phosphorylation by G1-Cdk1.
H2AFZ: A Novel Prognostic Marker in Canine Melanoma and a Predictive Marker for Resistance to CDK4/6 Inhibitor Treatment.
TGF-β/Activin Signaling Promotes CDK7 Inhibitor Resistance in Triple Negative Breast Cancer Cells through Upregulation of Multidrug Transporters.
Naturally Sourced CDK Inhibitors and Current Trends in Structure-Based Synthetic Anticancer Drug Design by Crystallography.
p53-GSDME Elevation: A Path for CDK7 Inhibition to Suppress Breast Cancer Cell Survival.

Cancer Cell. 2021 Aug 21. pii: S1535-6108(21)00447-5. [Epub ahead of print]

Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2.

Rinath Jeselsohn, Rachel Schiff, Albert Grinshpun.

Overcoming resistance to CDK4/6 inhibitors is a major clinical challenge. In this issue of Cancer Cell, Freeman-Cook et al. study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor.

DOI: https://doi.org/10.1016/j.ccell.2021.08.007
Nat Commun. 2021 Sep 10. 12(1): 5386

Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.

Fabin Dang, Li Nie, Jin Zhou, Kouhei Shimizu, Chen Chu, Zhong Wu, Anne Fassl, Shizhong Ke, Yuangao Wang, Jinfang Zhang, Tao Zhang, Zhenbo Tu, Hiroyuki Inuzuka, Piotr Sicinski, Adam J Bass, Wenyi Wei.

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

DOI: https://doi.org/10.1038/s41467-021-25700-6
JCO Precis Oncol. 2021 ;pii: PO.20.00445. [Epub ahead of print]5

Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib.

Aditya Bardia, Fei Su, Nadia Solovieff, Seock-Ah Im, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Kyung Hae Jung, Marco Colleoni, Rafael Villanueva Vázquez, Fabio Franke, Sara Hurvitz, Nadia Harbeck, Louis Chow, Tetiana Taran, Karen Rodriguez Lorenc, Naveen Babbar, Debu Tripathy, Yen-Shen Lu.

PURPOSE: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial.
METHODS: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib.
RESULTS: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status.
CONCLUSION: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

DOI: https://doi.org/10.1200/PO.20.00445
Int J Mol Sci. 2021 Sep 01. pii: 9514. [Epub ahead of print]22(17):

Docking to a Basic Helix Promotes Specific Phosphorylation by G1-Cdk1.

Ilona Faustova, Kaidi Möll, Ervin Valk, Mart Loog, Mihkel Örd.

  Cyclins are the activators of cyclin-dependent kinase (CDK) complex, but they also act as docking scaffolds for different short linear motifs (SLiMs) in CDK substrates and inhibitors. According to the unified model of CDK function, the cell cycle is coordinated by CDK both via general CDK activity thresholds and cyclin-specific substrate docking. Recently, it was found that the G1-cyclins of S. cerevisiae have a specific function in promoting polarization and growth of the buds, making the G1 cyclins essential for cell survival. Thus, while a uniform CDK specificity of a single cyclin can be sufficient to drive the cell cycle in some cells, such as in fission yeast, cyclin specificity can be essential in other organisms. However, the known G1-CDK specific LP docking motif, was not responsible for this essential function, indicating that G1-CDKs use yet other unknown docking mechanisms. Here we report a discovery of a G1 cyclin-specific (Cln1,2) lysine-arginine-rich helical docking motif (the K/R motif) in G1-CDK targets involved in the mating pathway (Ste7), transcription (Xbp1), bud morphogenesis (Bud2) and spindle pole body (Spc29, Spc42, Spc110, Sli15) function of S. cerevisiae. We also show that the docking efficiency of K/R motif can be regulated by basophilic kinases such as protein kinase A. Our results further widen the list of cyclin specificity mechanisms and may explain the recently demonstrated unique essential function of G1 cyclins in budding yeast.

Keywords:  SLiM; cyclin specificity; cyclin-dependent kinase; kinase specificity; phosphorylation

DOI:  https://doi.org/10.3390/ijms22179514
Front Vet Sci. 2021 ;8 705359

H2AFZ: A Novel Prognostic Marker in Canine Melanoma and a Predictive Marker for Resistance to CDK4/6 Inhibitor Treatment.

Laura Bongiovanni, Anneloes Andriessen, Serenella Silvestri, Ilaria Porcellato, Chiara Brachelente, Alain de Bruin.

  Uncontrolled proliferation is a key feature of tumor progression and malignancy. This suggests that cell-cycle related factors could be exploited as cancer biomarkers and that pathways specifically involved in the cell cycle, such as the Rb-E2F pathway, could be targeted as an effective anti-tumor therapy. We investigated 34 formalin-fixed paraffin-embedded (FFPE) tissue samples of canine cutaneous melanocytoma, cutaneous melanoma, and oral melanoma. Corresponding clinical follow-up data were used to determine the prognostic value of the mRNA expression levels of several cell cycle regulated E2F target genes (E2F1, DHFR, CDC6, ATAD2, MCM2, H2AFZ, GINS2, and survivin/BIRC5). Moreover, using four canine melanoma cell lines, we explored the possibility of blocking the Rb-E2F pathway by using a CDK4/6 inhibitor (Palbociclib) as a potential anti-cancer therapy. We investigated the expression levels of the same E2F target gene transcripts before and after treatment to determine the potential utility of these molecules as predictive markers. The E2F target gene H2AFZ was expressed in 91.43% of the primary tumors and H2AFZ expression was significantly higher in cases with unfavorable clinical outcome. Among the other tested genes, survivin/BIRC5 showed as well-promising results as a prognostic marker in canine melanoma. Three of the four tested melanoma cell lines were sensitive to the CDK4/6 inhibitor. The resistant cell line displayed higher expression levels of H2AFZ before treatment compared to the CDK4/6 inhibitor-sensitive cell lines. The present results suggest that CDK4/6 inhibitors could potentially be used as a new anti-cancer treatment for canine melanoma and that H2AFZ could serve as a prognostic and predictive marker for patient selection.

Keywords:  CDK4/6 inhibitor; E2F target genes; cancer biomarker; dog; melanoma

DOI:  https://doi.org/10.3389/fvets.2021.705359
J Biol Chem. 2021 Sep 02. pii: S0021-9258(21)00964-9. [Epub ahead of print] 101162

TGF-β/Activin Signaling Promotes CDK7 Inhibitor Resistance in Triple Negative Breast Cancer Cells through Upregulation of Multidrug Transporters.

Bryan M Webb, Benjamin L Bryson, Eduardo Williams-Medina, Jessica R Bobbitt, Darcie D Seachrist, Lindsey J Anstine, Ruth A Keri.

  Cyclin dependent kinase 7 (CDK7) is a master regulatory kinase that drives cell cycle progression and stimulates expression of oncogenes in a myriad of cancers. Inhibitors of CDK7 (CDK7i) are currently in clinical trials; however, as with many cancer therapies, patients will most likely experience recurrent disease due to acquired resistance. Identifying targets underlying CDK7i resistance will facilitate prospective development of new therapies that can circumvent such resistance. Here we utilized triple negative breast cancer (TNBC) as a model to discern mechanisms of resistance as it has been previously shown to be highly responsive to CDK7 inhibitors. After generating cell lines with acquired resistance, high throughput RNA-sequencing revealed significant upregulation of genes associated with efflux pumps and transforming growth factor-beta (TGF-β) signaling pathways. Genetic silencing or pharmacological inhibition of ABCG2, an efflux pump associated with multi-drug resistance, re-sensitized resistant cells to CDK7i, indicating a reliance on these transporters. Expression of activin A (INHBA), a member of the TGF-β family of ligands, was also induced, while its intrinsic inhibitor, follistatin (FST), was repressed. In resistant cells, increased phosphorylation of SMAD3, a downstream mediator, confirmed an increase in activin signaling, and phosphorylated SMAD3 directly bound the ABCG2 promoter regulatory region. Lastly, pharmacological inhibition of TGF-β/activin receptors or genetic silencing of SMAD4, a transcriptional partner of SMAD3, reversed the upregulation of ABCG2 in resistant cells and phenocopied ABCG2 inhibition. This study reveals that inhibiting the TGF-β/Activin-ABCG2 pathway is a potential avenue for preventing or overcoming resistance to CDK7 inhibitors.

Keywords:  ABCG2; CDK7; SY-1365; TGF-β; THZ1; TNBC; activin; cyclin dependent kinase 7; multidrug transporters; triple negative breast cancer

DOI:  https://doi.org/10.1016/j.jbc.2021.101162
Anticancer Agents Med Chem. 2021 Sep 07.

Naturally Sourced CDK Inhibitors and Current Trends in Structure-Based Synthetic Anticancer Drug Design by Crystallography.

Sisir Nandi, Rishita Dey, Sudatta Dey, Asmita Samadder, Anil Saxena.

  Cyclin-dependent kinases (CDKs) are the chief regulators in cell proliferation; the kinase activities are largely regulated by their interactions with CDK inhibitors (CKIs) and Cyclins. The association of different CDKs with CDKIs and Cyclins at the cell-cycle checkpoints of different stages of mitotic cell cycle function act more likely as the molecular switches that regulate different transcriptional events required for progression through the cell cycle. A fine balance in response to extracellular and intracellular signals is highly maintained in the orchestrated function of CDKs along with Cyclins and CDKIs for normal cell proliferation. This fine-tuning in mitotic cell cycle progression sometimes gets lost due to dysregulation of CDKs. The aberrant functioning of the CDKIs is therefore studied for its contributions as a vital hallmark of cancers. It has attracted our focus to maneuver cancer therapy. Hence, several synthetic CDKIs and their crystallography-based drug design have been explained to understand their mode of action with CDKs. Since most of the synthetic drugs function by inhibiting the CDK4/6 kinases by competitively binding to their ATP binding cleft, these synthetic drugs are reported to attack the normal, healthy growing cells adjacent to the cancer cells leading to the decrease in the life span of the cancer patients. The quest for traditional natural medicines may have a great impact on the treatment of cancer. Therefore, in the present studies, a search for naturally sourced CDK inhibitors has been briefly focused. Additionally, some synthetic crystallography-based drug design has been explained to elucidate different avenues to develop better anticancer chemotherapeutics, converting natural scaffolds into inhibitors of the CDK mediated abnormal signal transduction with lesser side effects.

Keywords:  Abnormal signaling; cancer; crystallography; natural CDK inhibitors; structure-based drug design

DOI:  https://doi.org/10.2174/1871520621666210908101751
Front Mol Biosci. 2021 ;8 697457

p53-GSDME Elevation: A Path for CDK7 Inhibition to Suppress Breast Cancer Cell Survival.

Yueyuan Wang, Jingyu Peng, Xuguang Mi, Ming Yang.

  Higher cyclin-dependent kinase (CDK7) expression is a character of breast cancer and indicates poor prognosis. Inhibiting CDK7 exhibited effective cancer cell suppression which implies the potential of CDK7 inhibition to be a method for anti-cancer treatment. Our study aimed to explore a novel mechanism of CDK7 inhibition for suppressing breast cancer cell survival. Here, we proved inhibiting CDK7 repressed breast cancer cell proliferation and colony formation and increased the apoptotic cell rate, with p53 and GSDME protein level elevation. When p53 was suppressed in MCF-7 cells, the decline of GSDME expression and associated stronger proliferation and colony formation could be observed. Since downregulation of GSDME was of benefit to breast cancer cells, p53 inhibition blocked the elevation of GSDME induced by CDK7 inhibition and retrieved cells from the tumor suppressive effect of CDK7 inhibition. Therefore, CDK7 inhibition exerted a negative effect on breast cancer cell proliferation and colony formation in a p53-GSDME dependent manner. These results revealed the CDK7-p53-GSDME axis could be a pathway affecting breast cancer cell survival.

Keywords:  CDK7; CDK7 inhibitor; GSDME; breast cancer; p53

DOI:  https://doi.org/10.3389/fmolb.2021.697457