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.; Penfold, Lucy; Ang, Simon; Ormrod, Alice; Ainscow, Edward; Bahl, Ash; Carling, David; Fuchter, Matthew J.; Ali, Simak; Bevan, Charlotte L.

doi:10.1101/2022.06.29.497030

Cited by 4 publications

(3 citation statements)

References 51 publications

(75 reference statements)

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“…Transcription of MNAT (MAT1) and CCNH (Cyclin H), additional components of the CAK complex, was also elevated in cells grown on LAF ECM. Increased expression of CDK7 is found in several cancers [36]; and CDK7 inhibition has shown promise in vitro against prostate [37], pancreatic [38], gastric [39] and breast cancer cells [40]. Further, a covalent inhibitor of CDK7, THZ1, showed efficacy against Tsc2 -null tumours in a mouse model [41].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix-Induced Genes May Reduce Response to Rapamycin in LAM

Clements,

Babaei-Jadidi,

Johnson

et al. 2024

Preprint

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Rationale. Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease driven by nodules containing TSC2-/- LAM cells and recruited LAM associated fibroblasts (LAFs). Although rapamycin reduces lung function loss, some patients continue to decline meaning additional therapies are needed. Objectives. To investigate how the LAM nodule environment affects LAM cell proliferation and the response to rapamycin. Methods. Changes in advanced LAM were identified using shotgun proteomics and immunohistochemistry in tissue from carefully phenotyped patients. Genes potentially associated with rapamycin insensitivity of cells grown on LAF-derived extracellular matrix were identified by RNA sequencing and validated using repurposed pharmacologic inhibitors. Main Results. More advanced disease was associated with increasing nodules adjacent to lung cysts and greater decline in forced expiratory volume in 1 sec (FEV1) when treated with rapamycin (p=0.005). In late-stage LAM, proteomics identified upregulation of pathways associated with accumulation of activated fibroblasts, including extracellular matrix deposition, glucose metabolism and the actin cytoskeleton. Picrosirius red staining and immunohistochemistry confirmed deposition of extracellular matrix within LAM nodules. The growth of TSC2-/- model LAM cells was increased on LAF-derived extracellular matrix (LAF ECM), and incompletely suppressed by rapamycin (p<0.0001). RNA sequencing of cells grown on LAF ECM identified upregulation of pathways driving cell cycle control, transcription and metabolism in cells. Tractable, pro-proliferative, rapamycin insensitive genes included CDK7, GAS6 and PLAU. Repurposed inhibitors of these pathways inhibited LAM cell proliferation and enhanced the anti-proliferative effect of rapamycin. Conclusions. Extracellular matrix deposited by LAM associated fibroblasts upregulates expression of genes which potentially blunt the response to rapamycin, but offer additional therapeutic opportunities for patients with established LAM.

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Section: Discussionmentioning

confidence: 99%

Extracellular Matrix-Induced Genes May Reduce Response to Rapamycin in LAM

Clements,

Babaei-Jadidi,

Johnson

et al. 2024

Preprint

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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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“…SNS-032, which inhibits CDK2, 7, and 9, has been evaluated for advanced solid tumors; however, the drug has not progressed further than phase I [16,17]. Recently, various CDK7-speci c inhibitors have been developed, such as BS-181 [18], ICEC0942 (CT7001; samuraciclib) [19][20][21], LY3405105 [22], LDC4297 [23], SY-1365 [24] (phase 1), THZ1 (SY-079) [25], THZ2 [6], YKL-5-124 [26], QS1189 [27], and SY-5609 [28]. Among them, SY-5609, THZ1, and THZ2 were tested preclinically against TNBC [6, 28].…”

Section: Introductionmentioning

confidence: 99%

Ibulocydine inhibits migration and invasion of TNBC cells via MMP-9 regulation

Kwon

Park

et al. 2023

Preprint

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Background Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating poor survival prognosis with more aggressive biology of rapidly progressive growth, metastasis to the lung, and short response duration to available therapies. TNBC is characterized by the negative expression of three hormone receptors. Therefore, compared to other breast cancers, TNBC is difficult to treat using hormone inhibitors and is resistant to chemotherapy. Additionally, the lack of effective targets limits the development of therapeutics. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed the following experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. Methods Colony-forming, cell counting kit-8 (CCK-8), wound healing, trans-well assays, and western blotting were performed in vitro. An experimental metastasis model was developed via intravenous injection of MDA-MB-231-Luc cells in vivo, and tumor growth was monitored using an In Vivo Imaging System (IVIS) spectrum. Results The result showed that IB reduced the viability of various TNBC cell lines in a dose-dependent manner. Pretreatment with z-VAD effectively blocked IB-induced cell death and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in TNBC cells. A reduction in the migration and invasion abilities of TNBC cell lines was observed following IB treatment in migration and invasion assays. We determined the expression levels of metastasis-related markers using western blotting and found that the expression of matrix metalloproteinase-9 (MMP-9) decreased in an IB dose-dependent manner. In addition, IB-induced inhibition of migration and invasion was blocked in MMP9-overexpressing MDA-MB-231-Luc cells. Results of in vivo experiments using the metastasis model showed that metastasis of MDA-MB-231-Luc cells to the lung was inhibited by IB. Conclusions Collectively, these results showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

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

Cited by 4 publications

References 51 publications

Extracellular Matrix-Induced Genes May Reduce Response to Rapamycin in LAM

Extracellular Matrix-Induced Genes May Reduce Response to Rapamycin in LAM

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

Ibulocydine inhibits migration and invasion of TNBC cells via MMP-9 regulation

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