Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response

摘要 而CDK4靶向药物(CDK4i)、帕波西利、阿贝西利和核糖核酸钙已显示出临床应用前景 在转移性乳腺癌(BC)的治疗中，缺乏伴随的诊断来识别反应 病人仍然是一个问题。虽然CDK4i治疗增加了一些患者的无进展生存期(PFS) 转移性高血压患者，许多患者表现出对CDK4/6抑制的原发耐药性，并且没有任何 从这些药物中受益，在6个月内改用化疗。鉴定生物标记物的研究进展 活性CDK4靶标的存在，从而使CDK4i敏感患者能够做出反应 转移性乳腺癌患者在治疗开始时要精准定位。因为CDK4/6是所有 致癌信号通路，这类药物也有可能在至少一个子集的 更多的肿瘤类型和CDK4i反应的生物标记物将加速这种 肿瘤类型的治疗类别，如转移性Her2、三阴性乳腺癌或卵巢癌， 几乎没有治疗选择。预测CDK4i疗效的生物标志物将意味着更快地受益 正确的患者，节省了成本和时间，减少了对不会受益的患者的毒性 在迫切需要新疗法的肿瘤类型中扩大这些疗法的使用。在……里面 本质：生物标记物将有助于将正确的药物提供给正确的患者。这个翻译项目将重点放在 一种新的诊断标记物p27Kip1 pY88用于识别对当前 采用CDK4i治疗。在发表和发表的工作中，我们已经证明了pY88是一种替代物 CDK4活性和CDK4i反应性的标记，在细胞系、原代外植体培养中，现在在 来自临床接受CDK4i治疗的患者的活组织检查。此RO1项目的目标是演示 P27Py是一种诊断生物标记物，用于识别CDK4/6I反应的患者，然后也 调和为什么Py可能通过将其与抗性机制相关联来划分抗性，与 这将进一步告知CDK4/6i药物的潜在用途。在目标1和目标2(翻译目标)中，我们 计划测试基于IHC的检测，以确定pY88是否可以作为预测重大PFS的生物标记物 CDK4/6I治疗对HR/HER2-BC患者的改善作用在目标3(机制目标)中，我们将 确定Py状态与CDK4/6i敏感性和阻力之间的关系。目标1：测试Py的能力 通过比较HR患者活检材料中pY88状态来预测有意义的PFS的生物标志物 BC使用CDK4/6i进行临床治疗，并提供患者结果数据。目的2.检验有效的Py检验在 来自两个已完成和正在进行的临床试验的临床相关队列。目标3：确定Py如何 状态与CDK4/6I敏感性和耐药性有关，通过使用生化研究来检测Py状态在 CDK4/6I耐药的体外和体内模型。

SUMMARY While the CDK4 targeting drugs (CDK4i), Palbociclib, Abemaciclib, and Ribociclib, have shown clinical promise in the treatment of metastatic breast cancer (BC), lack of a companion diagnostic to identify responsive patients remains a problem. While CDK4i therapy increases progression-free survival (PFS) in some metastatic HR+ patients, many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, switching to chemotherapy within 6 months. Development of a biomarker to identify the presence of the active CDK4 target, and therefore CDK4i sensitive patients, would enable responsive metastatic breast cancer patients to be pinpointed at the onset of therapy. As CDK4/6 is downstream of all oncogenic signaling pathways, it is also likely that this class of drugs will have efficacy in at least a subset of additional tumor types, and a biomarker for CDK4i responsiveness would accelerate the expansion of this class of therapy into tumor types, such as metastatic Her2+, Triple negative breast or ovarian cancer, which have few therapeutic options. A biomarker to predict effectiveness of CDK4i would mean more rapid benefit to the correct patients, a cost and time savings and reduced toxicity for patients who would not be benefited and extended use of these therapies across tumor types where novel therapies are desperately needed. In essence: a biomarker would help get the right drug to the right patients. This translational project will focus on the utility of a novel diagnostic marker, p27Kip1 pY88, to identify patients who would respond to the currently used CDK4i therapy. In published and presented work, we have shown that pY88 serves as a surrogate marker for CDK4 activity and in turn CDK4i responsiveness, in cell lines, primary explant culture, and now in biopsies from patients treated clinically with CDK4i therapy. The goal of this RO1 project is to demonstrate that p27 pY is a diagnostic biomarker to identify CDK4/6i-responsive patients and then also to reconcile why pY might demarcate resistance by associating it to mechanisms of resistance, with the idea that this will further inform potential uses of the CDK4/6i drugs. In Aims 1 and 2 (translational aims) we plan to test an IHC based assay to determine if pY88 can serve as a biomarker to predict significant PFS improvement in patients with HR+/HER2- BC treated with CDK4/6i. In Aim 3 (mechanism aim), we will determine how pY status relates to CDK4/6i sensitivity and resistance. Aim 1: To test the ability of the pY biomarker to predict significant PFS, by comparing pY88 status in biopsy material from patients with HR+ BC treated clinically with CDK4/6i with patient outcome data. Aim 2. To test the validated pY test in clinically relevant cohorts, from two completed and ongoing clinical trials. Aim 3: To determine how pY status relates to CDK4/6i sensitivity and resistance, by using biochemical studies to examine pY status in in vitro and in vivo models of CDK4/6i resistance.