Mcl-1 drives resistance of luminal breast cancers to targeted therapies

 描述(申请人提供)：bcl2家族蛋白使用复杂的家族内相互作用来调节内在的凋亡途径。尤其是抗凋亡的Bcl2家族成员(A1、Bcl2、BclxL、Bclw和Mcl-1)通过隔离促凋亡的Bcl2家族成员(Bak、Bax、Bid、Bim和Puma)来抑制细胞凋亡。因此，促进和抗凋亡的Bcl2蛋白的平衡调节了细胞的生死开关。在癌症中，抗凋亡的Bcl-2家族成员的持续过表达促进了肿瘤细胞的存活。此外，抗细胞凋亡的Bcl-2蛋白经常导致癌症对化疗和靶向治疗的耐药性。BH3-模拟物是一种小分子，旨在隔离抗凋亡的Bcl-2家族成员的活性，旨在对抗抗凋亡的Bcl-2蛋白引起的治疗耐药。在乳腺癌中，BH3类似物在一些但不是所有肿瘤中增加了治疗诱导的肿瘤细胞杀伤率。对这些BH3模拟物的潜在抗性机制尚不清楚。我们的初步数据表明，带有MCL1扩增的人源性乳腺癌细胞株对ABT-263的敏感性有限，ABT-263是一种类似BH3的靶向Bcl2、Bclxl和Bclw的细胞，经ABT-263处理后，Mcl-1蛋白的表达上调。MCL-1基因敲除增加了乳腺癌细胞对ABT-263的敏感性，而异位表达Mcl-1则增加了对ABT-263的耐药性。鉴于Bcl2家族在乳腺癌和其他癌症中的临床作用，进一步研究Mcl-1在ABT-263耐药中的作用是至关重要的，我们将在目标1中进行研究。我们进一步建议研究Mcl-1如何影响乳腺癌对雌激素剥夺的反应。大约65%的乳腺癌依赖于雌激素受体-a(ERA)信号，因此使用ERA靶向药物进行治疗。在这种情况下，McL-1的影响仍未得到研究。我们的初步数据显示，长期雌激素剥夺(LTED)后Mcl-1水平增加，LTED是一种用于模拟芳香酶抑制剂治疗引起的雌激素耗竭情况的模型。我们设计的目的是在AIM 2中对抗抗凋亡的Bcl-2蛋白引起的治疗耐药性。这些研究将共同确定Mcl-1抑制剂，包括我们的合作者开发的一种新的Mcl-1特异性BH3模拟物，是否可以在临床上用于提高肿瘤细胞的杀伤力和提高患者的生存时间。

 DESCRIPTION (provided by applicant): Bcl-2 family proteins use complex intra-family interactions to regulate the intrinsic apoptotic pathway. In particular, anti-apoptotic Bcl-2 famil members (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) inhibit apoptosis by sequestering pro-apoptotic Bcl-2 family members (Bak, Bax, Bid, Bim and Puma). Thus, the balance of pro- to anti-apoptotic Bcl-2 proteins regulates the cellular life-death switch. In cancers, sustained overexpression of anti-apoptotic Bcl-2 family members promotes tumor cell survival. Further, anti-apoptotic Bcl-2 proteins often drive resistance of cancers to chemotherapies and targeted therapies. BH3-mimetics, small molecules designed to sequester the activity of anti-apoptotic Bcl-2 family members, were designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins. In breast cancers, BH3-mimetics increase treatment-induced tumor cell killing in some but not all tumors. The mechanisms underlying resistance to these BH3-mimetics remain unclear. Our preliminary data suggest that human-derived breast cancer cell lines with MCL1 amplification display limited sensitivity to ABT-263, a BH3-mimetic targeting Bcl-2, Bcl-xL and Bcl-w, and up regulate Mcl-1 protein expression upon treatment with ABT-263. Mcl-1 knock-down increased sensitivity of breast cancer cells to ABT-263, while ectopic Mcl-1 expression enhanced ABT-263 resistance. Given the clinical impact of the Bcl-2 family in breast and other cancers, it is critical to investigate further the role of Mcl-1 in ABT-263 resistance, which we wil study in Aim 1. We further propose to study how Mcl-1 affects response of breast cancers to estrogen deprivation. Approximately 65% of breast cancers are dependent upon estrogen receptor-a (ERa) signaling, and thus are treated with ERa-targeting agents. The impact of Mcl-1 remains under-studied in this context. Our preliminary data show that Mcl-1 levels increase upon long term estrogen deprivation (LTED), a model used to mimic the estrogen-depleted conditions caused by treatment with aromatase inhibitors. We designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins in Aim 2. Together, these studies will determine if Mcl-1 inhibitors, including a novel Mcl-1- specific BH3-mimetic developed by our collaborator, could be exploited clinically to improve tumor cell killing and to increase patient survival.