Understanding divergent trial results of adjuvant CDK4/6 inhibitors for early stage breast cancer

Cunningham, Niamh; Turner, Nicholas C.

doi:10.1016/j.ccell.2021.02.011

Cited by 6 publications

(7 citation statements)

References 10 publications

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“…CDK4/6 inhibitors affect the progression of tumor cell cycle by inhibiting the enzyme complex (31). They have been used as first-line or second-line treatment in clinical trials for patients with HR-positive, HER2-negative, advanced breast cancer (32), and researchers have reported the results of their use in early-stage breast cancer (33). Experiments have shown that the application of CDK4/6 inhibitors is related to the improvement of protective immunity (34).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis

et al. 2022

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Background: In previous studies on the application of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy in advanced breast cancer, the outcomes of overall survival (OS) were inconsistent. This systematic review and meta-analysis aimed to further evaluate the clinical efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy on patients with hormone receptor (HR)positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.Methods: Randomized controlled trials (RCTs) comparing CDK4/6 inhibitors plus endocrine therapy and endocrine therapy alone in patients with HR-positive and HER2-negative advanced breast cancer were searched in the databases of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and China Science and Technology Journal Database (VIP) up to November 2022.Hazard ratios (HRs) and confidence intervals (CI) of OS, progression-free survival (PFS), the time from randomization to the first recorded disease progression while the patient was receiving next-line therapy or death from any cause (PFS2), time to first subsequent chemotherapy after discontinuation (TTC), and objective response rate (ORR), clinical benefit rate (CBR), safety indicators were extracted. Stata 14.0 software was used for meta analysis and the Cochrane risk-of-bias tool 2.0 was used to evaluate the bias risk.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis

et al. 2022

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“…6b). Interestingly, the highest efficacy was achieved with abemaciclib (IC 50 467 nM), a Cdk4/Cdk6 inhibitor, which was approved by the FDA in 2017 for the treatment of hormone receptor positive (HR+) and HER2-negative metastatic breast cancer [40][41][42] . Also, GSK1059615 (IC 50 1079 nM) and HTH-01-091 (IC 50 1597 nM) showed robust inhibition of HIPK3.…”

Section: Resultsmentioning

confidence: 99%

“…As ATP-competitive inhibitors target a structurally and functionally similar binding site, poly-pharmacology is often seen and this target promiscuity can lead to both advantageous and detrimental therapeutic consequences 45 . Abemaciclib, reported to be a selective CDK4/6 inhibitor 40 , is a third generation CDK-directed drug with an impressive clinical performance in the treatment of HR+ metastatic breast cancer [41][42][43] . However, it has been suggested early on that abemaciclib may exhibit pan-selective kinase inhibition properties that exceeds those of related CDK4/6 inhibitory drugs as palbociclib and ribociclib 43,46 .…”

Section: Discussionmentioning

confidence: 99%

Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation

et al. 2021

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Homeodomain-interacting protein kinases (HIPKs) belong to the CMGC kinase family and are closely related to dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). HIPKs are regulators of various signaling pathways and involved in the pathology of cancer, chronic fibrosis, diabetes, and multiple neurodegenerative diseases. Here, we report the crystal structure of HIPK3 in its apo form at 2.5 Å resolution. Recombinant HIPKs and DYRK1A are auto-activated and phosphorylate the negative elongation factor SPT5, the transcription factor c-Myc, and the C-terminal domain of RNA polymerase II, suggesting a direct function in transcriptional regulation. Based on a database search, we identified abemaciclib, an FDA-approved Cdk4/Cdk6 inhibitor used for the treatment of metastatic breast cancer, as potent inhibitor of HIPK2, HIPK3, and DYRK1A. We determined the crystal structures of HIPK3 and DYRK1A bound to abemaciclib, showing a similar binding mode to the hinge region of the kinase as observed for Cdk6. Remarkably, DYRK1A is inhibited by abemaciclib to the same extent as Cdk4/Cdk6 in vitro, raising the question of whether targeting of DYRK1A contributes to the transcriptional inhibition and therapeutic activity of abemaciclib.

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“…The development of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, abemaciclib, and ribociclib, was a substantive breakthrough in the treatment of ER-positive, HER2-negative breast cancer [ 10 , 11 ]. Palbociclib, approved by FDA in 2015, treated HR-positive, HER2-negative advanced breast cancer combined with an aromatase inhibitor (AI) as first-line treatment, or combined with fulvestrant in females who have undergone endocrine therapy (AI resistant-disease) [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Palbociclib sensitizes ER-positive breast cancer cells to fulvestrant by promoting the ubiquitin-mediated degradation of ER-α via SNHG17/Hippo-YAP axis

Lei,

Huang,

Shi

et al. 2023

Breast Cancer Res Treat

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Purpose Endocrine therapy is the anti-tumor therapy for human breast cancer but endocrine resistance was a major burden. It has been reported that Palbociclib and fulvestrant can be used in combination for the treatment of patients who are experiencing endocrine resistance. However, the underlying mechanism is unclear. In this study, we aimed to investigate the mechanism by which Palbocicilib affected ER-positive breast cancer, combined with fulvestrant. Methods We first detected the effect of palbociclib on cell survival, growth and cycle distribution separately by MTT, colony formation and flow cytometry. Then SNHG17 was screened as palbociclib-targeted LncRNA by LncRNA-seq, and the SNHG17-targeted mRNAs were selected by mRNA-seq for further determination. Subsequently, the underlying mechanism by which palbociclib promoted the cytotoxicity of fulvestrant was confirmed by qRT-PCR, western blot, and immunoprecipitation. Eventually, the xenograft model and immunohistochemistry experiments were used to validate the sensitization effect of palbociclib on fulvestrant and its mechanism in vivo. Results Palbociclib significantly enhanced the cytotoxicity of fulvestrant in fulvestrant-resistant breast cancer cell lines. Interestingly, this might be related to the lncRNA SNHG17 and the Hippo signaling pathway. And our subsequent western blotting experiments confirmed that overexpressing SNHG17 induced the down-regulation of LATS1 and up-regulated YAP expression. Furthermore, we found that the increased sensitivity of breast cancer cells was closely associated with the LATS1-mediated degradation of ER-α. The following animal experiments also indicated that overexpressing SNHG17 obviously impaired the anti-cancer effect of co-treatment of palbociclib and fulvestrant accompanied by decreased LATS1 and increased ER-α levels. Conclusion Palbociclib might sensitize the cytotoxicity of fulvestrant in ER-positive breast cancer cells by down-regulating SNHG17 expression, and then resulted in the LATS1-inactivated oncogene YAP and LATS1-mediated degradation of ER-α.

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Understanding divergent trial results of adjuvant CDK4/6 inhibitors for early stage breast cancer

Cited by 6 publications

References 10 publications

Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis

Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis

Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation

Palbociclib sensitizes ER-positive breast cancer cells to fulvestrant by promoting the ubiquitin-mediated degradation of ER-α via SNHG17/Hippo-YAP axis

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