The Potent Novel CDK4/6 Inhibitor TQB3616 in Hormone Receptor Positive Breast Cancer: Preclinical Characterization with in vitro and Human Tumor Xenograft Models.

IF 3.3 4区 医学 Q2 ONCOLOGY
Breast Cancer : Targets and Therapy Pub Date : 2023-12-08 eCollection Date: 2023-01-01 DOI:10.2147/BCTT.S434973
Wenyu Hu, Lei Wang, JiaLing Luo, Jian Zhang, Nanlin Li
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引用次数: 0

Abstract

Purpose: Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway exerts a considerable inhibitory effect, preventing the spread and metastasis of breast cancer cells and promoting tumor regression. In this study, we examined the antitumor activity of TQB3616, a novel inhibitor of CDK4/6 activity, which showed a greater efficacy improvement in antitumor effects.

Methods: TQB3616 group, abemaciclib group and endocrine or HER-2 targeted combination therapy group were set up respectively. The effects of drugs on cell proliferation activity, cell cycle, apoptosis, downstream protein expression and gene expression of HR positive (T47D, MCF-7) and HER-2 positive (BT474, MDA-MB-361) breast cancer cell lines were studied. The antiproliferative effect of TQB3616 was also measured in vivo.

Results: TQB3616 showed a remarkable inhibitory effect on the proliferation of hormone receptor-positive breast cancer cells in vitro. In addition, TQB3616 combined with endocrine therapy or Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy showed significant synergistic antitumor activity in estrogen receptor (ER)-positive/HER2-negative or HER2-positive breast cancer. In contrast to abemaciclib, which targets the CDK4/6 pathway with proven efficacy, the oral agent TQB3616 not only induced G1 stalling, leading to a profound reduction in the level of RB protein phosphorylated at Ser807/811, but also showed enhanced tumor killing effects by promoting cell apoptosis. Oral administration of TQB3616 showed more potent antitumor activity than abemaciclib in an in vitro breast cancer xenograft model, causing significant tumor regression associated with sustained target inhibition in tumor tissue and manageable in vivo toxicity.

Conclusion: The results of this study indicate that TQB3616 is a novel CDK4/6 inhibitor, and its highly effective antitumor activity against breast cancer is expected to yield promising therapeutic effects in clinical studies.

治疗激素受体阳性乳腺癌的强效新型 CDK4/6 抑制剂 TQB3616:体外和人类肿瘤异种移植模型的临床前特征描述
目的:抑制细胞周期蛋白依赖性激酶(CDK)4/6-视网膜母细胞瘤(RB)通路具有相当大的抑制作用,可阻止乳腺癌细胞的扩散和转移,促进肿瘤消退。本研究考察了新型CDK4/6活性抑制剂TQB3616的抗肿瘤活性,发现其在抗肿瘤效果方面有较大的疗效提高:方法:分别设立TQB3616组、abemaciclib组和内分泌或HER-2靶向联合治疗组。研究了药物对HR阳性(T47D、MCF-7)和HER-2阳性(BT474、MDA-MB-361)乳腺癌细胞株的细胞增殖活性、细胞周期、细胞凋亡、下游蛋白表达和基因表达的影响。此外,还测定了 TQB3616 在体内的抗增殖作用:结果:TQB3616 对体外激素受体阳性乳腺癌细胞的增殖有显著的抑制作用。此外,TQB3616与内分泌疗法或人类表皮生长因子受体2(HER2)靶向疗法联合使用,对雌激素受体(ER)阳性/HER2阴性或HER2阳性乳腺癌具有显著的协同抗肿瘤活性。abemaciclib靶向CDK4/6通路的疗效已得到证实,与之相比,口服药物TQB3616不仅能诱导G1停滞,导致在Ser807/811处磷酸化的RB蛋白水平显著下降,还能通过促进细胞凋亡增强杀瘤效果。在体外乳腺癌异种移植模型中,口服 TQB3616 比阿巴西利(abemaciclib)显示出更强的抗肿瘤活性,在肿瘤组织中引起显著的肿瘤消退,并具有持续的靶点抑制作用和可控的体内毒性:本研究结果表明,TQB3616是一种新型CDK4/6抑制剂,其对乳腺癌的高效抗肿瘤活性有望在临床研究中产生良好的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.10
自引率
0.00%
发文量
40
审稿时长
16 weeks
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