Effect of CX4945 in tamoxifen resistant BCa

非基因组雌激素信号转导机制与抗雌激素治疗耐药有关 乳腺癌的治疗方法及其对选择性雌激素受体促分裂作用的影响 调制器(SERM)。ERα36[雌激素受体α的36 kD转录变异体(ERα)]介导非 基因组雌激素信号转导，并参与抗雌激素抵抗和抗雌激素诱导 有丝分裂1.ERα66(全长ERα)和ERα36信号的双重抑制可能被证明是更 有效的抗激素治疗模式，避免获得抗雌激素诱导的耐药性和 肿瘤发生学。这可以通过对常见的翻译后调控进行药理学靶向来实现 两种异构体之间的机制(即，磷酸化)。CX4945(Silmitasertib)，临床分期CK2 抑制剂，抑制ERα66和ERα36的蛋白水平。因此，CX4945可能用于独特地扰乱 致癌激酶信号转导以及降低ERα异构体在胆道中的稳定性。我们假设CX4945 通过发挥间接泛雌激素受体的作用，抑制基因组和非基因组雌激素信号 下调，干扰ERα66和ERα36在Bca中的表达。 为了检验这一假设，我们将： 目的I.研究ERα66/36/CK2信号轴在三苯氧胺耐药中的作用。 为此，我们假设CK2通过促进异常的ERα促进4HT耐药的发生 发信号。我们将确定ERα36和CK2表达改变在 乳腺癌患者对他莫昔芬耐药性的研究进展。 目的2探讨CX4945下调基底动脉内皮细胞ERα66/36表达的机制。在这里我们 推测CX4945对CK2的药理抑制使ERα亚型对26S易感 蛋白酶体降解途径。我们将确定CK2介导的ERα66/36磷酸化对 伴侣相互作用、泛素化以及随后ERα36的蛋白降解。 目的3评价CX4945在结对患者来源的异种移植(PDX)模型中的抗肿瘤作用。 BCA的4HT敏感和耐药模型。我们假设CX4945将抑制肿瘤的进展。 他莫昔芬敏感和耐药(原发和获得性)PDX肿瘤。内分泌性PDX肿瘤 敏感的患者将被用来产生获得性抵抗的模型，而从头抵抗将被用来 用Y537S突变患者的PDX建模。 这些研究的成功完成可能导致CX4945或类似的CK2抑制剂在间接 PAN-ERα下调在激素敏感和激素抵抗乳腺癌治疗中的作用

Non-genomic estrogen signaling has been implicated in mediating therapeutic resistance to anti-estrogen therapies in breast carcinoma (BCa) and may contribute to the mitogenic effects of selective estrogen receptor modulators (SERMS). ERα36 [a 36 Kd transcript variant of estrogen receptor alpha (ERα)] mediates non- genomic estrogen signaling, and is implicated in anti-estrogen resistance and anti-estrogen induced mitogenesis1. Dual inhibition of ERα66 (full length ERα) and ERα36 signaling might prove to be a more efficacious mode of antihormonal therapy that avoids the acquisition of anti-estrogen induced resistance and tumorigenesis. This can be achieved by pharmacological targeting of the common posttranslational regulatory mechanisms (ie, phosphorylation) between the two isoforms. CX4945 (silmitasertib), a clinical stage CK2 inhibitor, represses protein levels of both ERα66 and ERα36. As such CX4945 might serve to uniquely disrupt oncogenic kinase signaling as well as reduces stability of ERα isoforms in BCa. We hypothesize that CX4945 inhibits both genomic and nongenomic estrogenic signaling by functioning as an indirect pan-estrogen receptor downregulator which disrupts both ERα66 and ERα36 expression in BCa. In order to test this hypothesis we will: Aim I. Investigate the role of the ERα66/36 /CK2 signaling axis in the development of tamoxifen resistance. For this aim we hypothesize that CK2 promotes the development of 4HT resistance by promoting aberrant ERα signaling. We will determine the incidence and causative role of altered ERα36 and CK2 expression in the development of tamoxifen resistance in breast cancer. Aim 2 Elucidate the mechanisms of CX4945 mediated downregulation of ERα66/36 in BCa. Here we hypothesize that pharmacological inhibition of CK2 with CX4945 renders ERα isoforms susceptible to the 26S proteasomal degradation pathway. We will ascertain the impact of CK2 mediated phosphorylation of ERα66/36 on chaperone interaction, ubiquitination and subsequently the proteolytic degradation of ERα36. Aim 3 Assess the antineoplastic efficacy of CX4945 in paired patient derived xenograft (PDX) models of 4HT sensitive and resistant models of BCa. We hypothesize that CX4945 will inhibit the progression of tamoxifen-sensitive and tamoxifen-resistant (de novo and acquired) PDX tumors. PDX tumors from endocrine sensitive patients will be used to generate models of acquired resistance, whereas de-novo resistance will be modelled using PDX from patients with Y537S mutation. The successful completion of these studies could lead to the use of CX4945 or similar CK2 inhibitors with indirect pan-ERα downregulating functions in the treatment of hormone sensitive and hormone resistant breast cancer.