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

 描述（由申请人提供）：Bcl-2家族蛋白使用复杂的家族内相互作用来调节内在凋亡途径。特别地，抗凋亡Bcl-2家族成员（A1、Bcl-2、Bcl-xL、Bcl-w和Mcl-1）通过隔离促凋亡Bcl-2家族成员（巴克、Bax、Bid、Bim和Puma）来抑制凋亡。因此，促凋亡Bcl-2蛋白与抗凋亡Bcl-2蛋白的平衡调节细胞生死开关。在癌症中，抗凋亡Bcl-2家族成员的持续过表达可促进肿瘤细胞的存活。此外，抗凋亡Bcl-2蛋白通常会导致癌症对化疗和靶向治疗产生抗性。BH 3-模拟物，设计用于隔离抗凋亡Bcl-2家族成员的活性的小分子，被设计用于对抗由抗凋亡Bcl-2蛋白引起的治疗抗性。在乳腺癌中，BH 3模拟物在一些但不是所有肿瘤中增加治疗诱导的肿瘤细胞杀伤。对这些BH 3-模拟物的抗性的潜在机制仍不清楚。 我们的初步数据表明，MCL 1扩增的人源性乳腺癌细胞系对ABT-263（一种靶向Bcl-2、Bcl-xL和Bcl-w的BH 3模拟物）显示出有限的敏感性，并在用ABT-263处理后上调Mcl-1蛋白表达。Mcl-1敲低增加乳腺癌细胞对ABT-263的敏感性，而异位Mcl-1表达增强ABT-263抗性。鉴于Bcl-2家族在乳腺癌和其他癌症中的临床影响，进一步研究Mcl-1在ABT-263抗性中的作用至关重要，我们将在目标1中研究。 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-α（ER α）信号传导，因此用ER α靶向剂治疗。在这种情况下，Mcl-1的影响仍然研究不足。我们的初步数据显示，Mcl-1水平增加后，长期雌激素剥夺（LTED），用于模拟雌激素耗竭的条件下，由芳香酶抑制剂治疗引起的模型。我们设计对抗Aim 2中抗凋亡Bcl-2蛋白引起的治疗抗性。总之，这些研究将确定Mcl-1抑制剂，包括我们的合作者开发的新型Mcl-1特异性BH 3模拟物，是否可以在临床上用于改善肿瘤细胞杀伤和增加患者存活率。

 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.