Abstract P6-20-13: The pure progesterone receptor (PR) antagonist onapristone enhances the anti-proliferative effects of CDK4/6 inhibitors in preclinical in-vitro breast cancer models

D. Lala, T. Haque, H. Feinman, J. Wu, Y. Wang, A. Dwyer, Thu H. Truong, C. Lange
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引用次数: 1

Abstract

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer related death in women. Around 5–10% of cases are metastatic at diagnosis, and close to 30% of patients with early stage disease will relapse with metastatic disease. Anti-estrogen therapy is an important treatment modality for hormone receptor-positive (HR+) metastatic breast cancer (mBCa) as mono- or combination (e.g. with CDK4/6 inhibitors) first-line (1L) therapy. Unfortunately, despite the high rate of clinical benefit in 1L therapy, disease progression still generally occurs and there remains a need for an efficacious 2L therapy. Although anti-estrogens continue to play a role in 2L treatment there is a critical need for targeting additional mechanisms in combination with anti-estrogens. Progesterone is a major mitogen in the adult human mammary epithelium and, in addition to ER, is a key driver of breast cancer cell proliferation. Thus, blocking both ER and PR would likely be an effective approach for inhibition of all hormone driven breast cancer cell proliferation. Onapristone is a unique PR full antagonist that is efficacious as an antitumor agent in multiple preclinical breast cancer models and exhibits additive/synergistic effects with antiestrogens. Here, we examine the effects of onapristone in in-vitro model systems in combination with CDK4/6 inhibitors. Methods: T47D cells were treated with various concentrations of onapristone or palbociclib in media containing 10%FBS.10 days after treatment cell viability was determined using Cell Titer Glo. Cells were also treated with increasing concentrations of palbociclib in the absence or presence of onapristone and analysed for cell proliferation after 10 days and for gene expression after 3 days of treatment.The effects of onapristone were also tested in soft agar anchorage-independent growth assays as well as 3D tumorsphere assays using ER+/PR+ MCF7 and BT474 cells -/+ onapristone for 21-28 days. Formed colonies or spheres were analyzed morphologically using cell stain and by quantifying the total number and size of colonies or spheres formed. Results:Onapristone inhibited T47D cell proliferation in a concentration-dependent manner. Additionally, it sensitized the cells to inhibition by CDK4/6 inhibitors in the preclinical in-vitro models. Onapristone also had a marked effect on downstream target genes in the cell-based models providing a mechanistic basis for the anti-proliferative effects. Onapristone also blocked progesterone-induced breast cancer cell survival in either soft agar or 3D tumorsphere assays with effects comparable to that of anti-estrogen (fulvestrant). Conclusions: Onapristone inhibits T47D proliferation and key target genes involved in cell proliferation. Additionally, onapristone enhances the anti-proliferative effects of palbociclib in-vitro. Previous studies have provided a clear rationale for combining onapristone and anti-estrogens in the clinic for the treatment of breast cancer. Our data extend these studies to provide additional rationale for the combination of onapristone with CDK4/6 inhibitors such as palbociclib as an effective new approach for the treatment of breast cancer. Citation Format: Lala D, Haque T, Feinman H, Wu J, Wang Y, Dwyer A, Truong T, Lange C. The pure progesterone receptor (PR) antagonist onapristone enhances the anti-proliferative effects of CDK4/6 inhibitors in preclinical in-vitro breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-13.
摘要P6-20-13:纯孕激素受体(PR)拮抗剂onapristone在临床前体外乳腺癌模型中增强了CDK4/6抑制剂的抗增殖作用
乳腺癌是最常见的癌症,也是妇女癌症相关死亡的第二大原因。约5-10%的病例在诊断时已转移,近30%的早期疾病患者会复发并转移性疾病。抗雌激素治疗是激素受体阳性(HR+)转移性乳腺癌(mBCa)的重要治疗方式,可作为单用或联合(如与CDK4/6抑制剂)一线(1L)治疗。不幸的是,尽管1L治疗的临床获益率很高,但疾病进展仍然普遍发生,仍然需要有效的2L治疗。尽管抗雌激素继续在2L治疗中发挥作用,但迫切需要靶向与抗雌激素联合的其他机制。黄体酮是成人乳腺上皮中主要的有丝分裂原,除ER外,也是乳腺癌细胞增殖的关键驱动因素。因此,阻断ER和PR可能是抑制所有激素驱动的乳腺癌细胞增殖的有效方法。奥纳匹司通是一种独特的PR全拮抗剂,在多种临床前乳腺癌模型中作为抗肿瘤药物有效,并与抗雌激素具有加性/协同作用。在这里,我们研究了onapristone在体外模型系统中与CDK4/6抑制剂联合使用的效果。方法:在含10%胎牛血清的培养基中,用不同浓度的奥那匹司酮或帕博西尼处理T47D细胞。治疗10天后用细胞滴度Glo检测细胞活力。在没有或存在奥那匹司酮的情况下,细胞也用增加浓度的帕博西尼处理,并在10天后分析细胞增殖和在治疗3天后分析基因表达。使用ER+/PR+ MCF7和BT474细胞-/+ onapristone 21-28天,在软琼脂锚定不依赖生长试验和3D肿瘤球试验中检测onapristone的作用。形成的菌落或球体使用细胞染色和定量的总数和大小形成的菌落或球体的形态分析。结果:奥那匹司酮抑制T47D细胞增殖呈浓度依赖性。此外,在临床前体外模型中,它使细胞对CDK4/6抑制剂的抑制变得敏感。在基于细胞的模型中,奥纳匹司通对下游靶基因也有显著的影响,为其抗增殖作用提供了机制基础。在软琼脂或3D肿瘤球试验中,奥纳匹司通也能阻断黄体酮诱导的乳腺癌细胞存活,其效果与抗雌激素(氟维司汀)相当。结论:奥那普利斯通抑制T47D增殖及参与细胞增殖的关键靶基因。此外,onapristone在体外增强了palbociclib的抗增殖作用。以往的研究已经为临床应用奥纳匹司酮和抗雌激素联合治疗乳腺癌提供了明确的依据。我们的数据扩展了这些研究,为onapristone联合CDK4/6抑制剂(如palbociclib)作为治疗乳腺癌的有效新方法提供了额外的理论依据。引用本文:Lala D, Haque T, Feinman H, Wu J, Wang Y, Dwyer A, Truong T, Lange C.纯孕激素受体(PR)拮抗剂onapristone增强CDK4/6抑制剂在临床前体外乳腺癌模型中的抗增殖作用[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;癌症杂志,2019;79(4增刊):P6-20-13。
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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