The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

Constantin, Theodora A.; Varela-Carver, Anabel; Greenland, Kyle K; Almeida, Gilberto S.; Olden, Ellen; Penfold, Lucy; Ang, Simon; Ormrod, Alice; Leach, Damien A.; Lai, Chun‐Fui; Ainscow, Edward; Bahl, Ash; Carling, David; Fuchter, Matthew J.; Ali, Simak; Bevan, Charlotte L.

doi:10.1038/s41416-023-02252-8

Cited by 8 publications

(4 citation statements)

References 55 publications

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“…We also discovered that FERMT1 was highly expressed in PC tissues and cells, and the expression level of FERMT1 was signi cantly correlated with the Gleason score of PC patients, suggesting that FERMT1 might be involved in the progression of human PC. It is widely recognized that LNCaP and C4-2 cells exhibit androgen receptor (AR) positivity, while DU145 and PC3 cells lack AR expression 29 . Previous studies have shown that LNCaP is an androgen-responsive cell line, whereas C4-2, PC3, and DU145 are androgen-independent cell lines 30,31 .…”

Section: Discussionmentioning

confidence: 99%

FERMT1 contributes to the progression of prostate cancer through the p53 pathway

Sun,

Fu,

Chen

2024

Preprint

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Purpose Fermitin family member 1 (FERMT1) is associated with the progression of different types of cancer. However, its biological functions of FERMT1 in prostate cancer (PC) are unclear. In this study, we preliminarily investigated the roles of FERMT1 and the mechanism by which it regulates the progression of PC. Methods The expression level of FERMT1 in PC tissues and cells was evaluated by immunohistochemical staining and Western blotting (WB) assay, respectively. Celigo cell count, cell counting kit-8 (CCK-8), flow cytometry, wound healing, Transwell assays and a mouse xenograft model was performed to evaluate the roles of FERMT1 in PC in vitro and in vivo. The interaction between p53 and FERMT1 was further investigated through co-immunoprecipitation (Co-IP). Finally, cells were treated with pifithrin-α (PFT-α), a p53 inhibitor, to investigate the regulatory role of p53 in the FERMT1-mediated progression of PC. Results FERMT1 was found to be upregulated in PC tissues and cells. Knocking down FERMT1 inhibited proliferation, migration, and cell cycle progression, and induced apoptosis in DU145 and LNCaP cell lines. Deleting FERMT1 also suppressed tumor growth of PC xenografts in vivo. More importantly, FERMT1 was discovered to play a significant role in cellular functions via the p53 signaling pathway, and the effects of FERMT1 knockdown on PC cellular function could be attenuated by pifithrin-α, a p53-inhibitor. Conclusions These findings of this study indicated that FERMT1 silencing partially inhibited PC progression via the p53 signaling pathway. Thus, FERMT1 is a promising potential therapeutic target for treating PC.

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Section: Discussionmentioning

confidence: 99%

FERMT1 contributes to the progression of prostate cancer through the p53 pathway

Sun,

Fu,

Chen

2024

Preprint

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“…Previous studies also showed that CDK7 inhibition can mediate p53-induced apoptosis. However, in these published studies, evidence of increased apoptosis was seen with either high concentrations of the CDK7i ( 48 ) or in combination with a second drug ( 49 ). This raises the possibility that this effect may be off target and requires additional investigation.…”

Section: Discussionmentioning

confidence: 99%

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer

Guarducci,

Nardone,

Russo

et al. 2024

Clinical Cancer Research

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Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER) positive (ER+) breast cancer (BC). Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine resistant ER+ BC models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ BC. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ BC remain elusive. Herein, we sought to unravel these mechanisms. Experimental Design: We conducted multi-omic analyses in ER+ BC models in vitro and in vivo including models with different genetic backgrounds. We also performed genome wide CRISPR knock-out library screens to identify potential therapeutic vulnerabilities in CDK4/6i resistance models. Results: We found that the on-target anti-tumor effects of CDK7 inhibition in ER+ BC are in part p53 dependent, involve cell-cycle inhibition and suppression of c-MYC. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ETs and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118, however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Lastly, genome wide CRISPR/Cas9 screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i resistant models. Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ BC. In addition, our study highlights the potential of increased MYC activity and intact P53 as predictors for sensitivity to CDK7 inhibitor-based treatments.

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“…For the above reasons, we chose these three CDK inhibitors: abemaciclib (ABE, CDK4/6 inhibitor), fadraciclib (FAD, CDK2 inhibitor), and samuraciclib (SAM, CDK7 inhibitor) in TNBC model for clinical translation. 22,23…”

Section: Introductionmentioning

confidence: 99%

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

Wu,

Wang,

Gao

et al. 2024

Cancer

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BackgroundClinical studies on programmed death‐ligand 1 (PD‐L1) immune checkpoint inhibitors for treating triple‐negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor‐infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin‐dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies.MethodsThe authors tested three CDK inhibitors on the TNBC cell lines MDA‐MB‐231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune‐related mechanisms of different combination therapy experiments in a 4T1 cell‐transplanted BALB/c mouse model.ResultsTreatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell‐cycle arrest and induced apoptosis in human breast cancer MDA‐MB‐231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD‐L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels.ConclusionsCombination therapy with CDK and PD‐L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

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The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

Cited by 8 publications

References 55 publications

FERMT1 contributes to the progression of prostate cancer through the p53 pathway

FERMT1 contributes to the progression of prostate cancer through the p53 pathway

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

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