Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

Attia, Yasmin M.; Shouman, Samia A.; Salama, Salama A.; Ivan, Cristina; Elsayed, Abdelrahman M.; Amero, Paola; Rodríguez-Aguayo, Cristian; López-Berestein, Gabriel

doi:10.3390/ijms21082974

Cited by 18 publications

(13 citation statements)

References 59 publications

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“…Finally, we measured the levels of several drug resistance-, tumorigenesis-, and mitotic-related proteins after rescuing hnRNPU-WT or hnRNPU-4KR ( Figure 6 i and Supplementary Figure S5d ). We showed that the rescue of hnRNPU-WT increases the level of drug resistance- or tumorigenesis-related proteins, such as CDK7 [ 44 , 45 ] or FoxM1 [ 46 ] ( Figure 6 i). Thus, the modulation of the CDC20–hnRNPU axis could improve the chromatin condensation in TNBC, which in turn resensitizes cellular drug response.…”

Section: Resultsmentioning

confidence: 99%

CDC20-Mediated hnRNPU Ubiquitination Regulates Chromatin Condensation and Anti-Cancer Drug Response

Wavelet-Vermuse

Odnokoz

Xue

et al. 2022

Cancers

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Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator. It plays an important role in cancer development and drug resistance. However, the molecular mechanisms by which CDC20 regulates cellular drug response remain poorly understood. Chromatin-associated CDC20 interactome in breast cancer cells was analyzed by using affinity purification coupled with mass spectrometry. hnRNPU as a CDC20 binding partner was validated by co-immunoprecipitation and immunostaining. The molecular domain, comprising amino acid residues 461–653, on hnRNPU required for its interaction with CDC20 was identified by mapping of interactions. Co-immunoprecipitation showed that CDC20-mediated hnRNPU ubiquitination promotes its interaction with the CTCF and cohesin complex. The effects of CDC20–hnRNPU on nuclear size and chromatin condensation were investigated by analyzing DAPI and H2B-mCherry staining, respectively. The role of CDC20–hnRNPU in tumor progression and drug resistance was examined by CCK-8 cell survival and clonogenic assays. Our study indicates that CDC20-mediated ubiquitination of hnRNPU modulates chromatin condensation by regulating the interaction between hnRNPU and the CTCF–cohesin complex. Dysregulation of the CDC20–hnRNPU axis contributes to tumor progression and drug resistance.

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Section: Resultsmentioning

confidence: 99%

CDC20-Mediated hnRNPU Ubiquitination Regulates Chromatin Condensation and Anti-Cancer Drug Response

Wavelet-Vermuse

Odnokoz

Xue

et al. 2022

Cancers

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“…We therefore attempted to target another cyclin-dependent kinase, CDK7, which is also involved in regulating the cell cycle [ 43 , 56 ]. CDK7 has been identified as a suitable target in drug-resistant BCs and effectively inhibits proliferation of TNBC cells in vitro [ 41 , 57 , 58 ]. Moreover, its specific targeting of tumour cells in vivo with no adverse effects on liver and kidney function were associated with the CDK7i [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

The CDK4/6 Inhibitor Palbociclib Inhibits Estrogen-Positive and Triple Negative Breast Cancer Bone Metastasis In Vivo

Saleh

Ottewell

Brown

et al. 2023

Cancers

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CDK 4/6 inhibitors have demonstrated significant improved survival for patients with estrogen receptor (ER) positive breast cancer (BC). However, the ability of these promising agents to inhibit bone metastasis from either ER+ve or triple negative BC (TNBC) remains to be established. We therefore investigated the effects of the CDK 4/6 inhibitor, palbociclib, using in vivo models of breast cancer bone metastasis. In an ER+ve T47D model of spontaneous breast cancer metastasis from the mammary fat pad to bone, primary tumour growth and the number of hind limb skeletal tumours were significantly lower in palbociclib treated animals compared to vehicle controls. In the TNBC MDA-MB-231 model of metastatic outgrowth in bone (intracardiac route), continuous palbociclib treatment significantly inhibited tumour growth in bone compared to vehicle. When a 7-day break was introduced after 28 days (mimicking the clinical schedule), tumour growth resumed and was not inhibited by a second cycle of palbociclib, either alone or when combined with the bone-targeted agent, zoledronic acid (Zol), or a CDK7 inhibitor. Downstream phosphoprotein analysis of the MAPK pathway identified a number of phosphoproteins, such as p38, that may contribute to drug-insensitive tumour growth. These data encourage further investigation of targeting alternative pathways in CDK 4/6-insensitive tumour growth.

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“…66 Cyclin-dependent kinase 7 (CDK7) inhibitors are emerging as promising BC drugs, being effective for HR+ BC in vitro and in vivo. 67,68 A Phase I trial (NCT03363893) of patients pretreated with CDK4/6 inhibitors is ongoing.…”

Section: Other Targetsmentioning

confidence: 99%

Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

Li¹,

Li²

2021

OTT

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Approximately 70% of breast cancer (BC) cases are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have acted as star drugs for reversing endocrine therapy (ET) resistance and improving the prognosis of patients with HR+ advanced breast cancer (ABC) since they were initially approved. However, progression eventually occurs. In this review, we summarize the recent treatment strategies post CDK4/6 inhibitors: 1) CDK4/6 inhibitors plus exemestane and everolimus; 2) phosphoinositide-3-kinase (PI3K) inhibitor alpelisib plus fulvestrant for patients with PIK3CA mutation; 3) poly (ADP-ribose) polymerase (PARP) inhibitor for patients with germline PALB2 mutations, somatic BRCA1/2 mutations, or germline BRCA1/2 mutations; 4) exemestane and everolimus; and (5) chemotherapy. These strategies are all supported by evidence from clinical trials and retrospective studies. We also describe potential future treatment strategies post CDK4/6 inhibitors, such as the trophoblast cell surface antigen 2 (Trop-2) directed antibody–drug conjugate, cyclin-dependent kinase 7 (CDK7) inhibitors, and B-cell lymphoma-2 (BCL-2) inhibitors.

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Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

Cited by 18 publications

References 59 publications

CDC20-Mediated hnRNPU Ubiquitination Regulates Chromatin Condensation and Anti-Cancer Drug Response

CDC20-Mediated hnRNPU Ubiquitination Regulates Chromatin Condensation and Anti-Cancer Drug Response

The CDK4/6 Inhibitor Palbociclib Inhibits Estrogen-Positive and Triple Negative Breast Cancer Bone Metastasis In Vivo

Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

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