Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer

靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7

基本信息

批准号：
10112834
负责人：
Nupam P Mahajan
金额：
$ 33.87万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-20 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112834
关键词：
ACK1 Gene AR gene ASH2L gene Ablation Address Androgen Antagonists Androgen Receptor Androgens Automobile Driving C-terminal Cancer Patient Cells ChIP-seq Chromatin Chromatin Remodeling Factor Complex DNA Polymerase II Data Dependence Deposition Disease Disease Progression Drug Kinetics Drug resistance Epigenetic Process Excretory function Exhibits Feedback Gap Junctions Gene Amplification Gene Expression Generations Genes Genetic Genetic Transcription Histone H4 Histone-Lysine N-Methyltransferase Homeostasis Human Investigational Drugs LNCaP Length Ligand Binding Domain MLL2 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Messenger RNA Metabolism Metastatic Prostate Cancer Methylation Methyltransferase Mus Neoplasm Metastasis Nucleosomes Oncogenes Pathogenesis Pathologic Phosphorylation Play Process Production Prostate Cancer therapy Protein Tyrosine Kinase RNA RNA Splicing Reader Recurrent disease Research Personnel Resistance Role Signal Transduction Site Transcription Coactivator Transcriptional Regulation Tyrosine Variant abiraterone absorption advanced prostate cancer androgen deprivation therapy anticancer research base cBioPortal candidate selection castration resistant prostate cancer clinical translation combat drug metabolism efficacy testing epigenetic regulation genome-wide histone methyltransferase histone modification in vivo ineffective therapies inhibitor/antagonist lead candidate mRNA Expression male mutant neoplastic novel novel therapeutics overexpression programs prostate cancer cell prostate cancer model prostate cancer progression receptor recruit response small molecule inhibitor treatment strategy tumor tumor growth tumor xenograft

项目摘要

Abstract For over half a century, prostate cancer research has focused on the Androgen receptor (AR), its role in the initiation of the disease and progression to the highly metastatic stage, castration resistant prostate cancer (CRPC). While AR antagonists such as enzalutamide or androgen- synthesis inhibitor abiraterone dampen AR functional activity, these are often ineffective long term, as the recalcitrant disease recurs within 2-3 years. CRPCs not only thrive under low or castrate levels of androgen, but also fastidiously maintain functional AR. Consequently, anti- androgen-resistance has become one of the most vexing problems in prostate cancer therapy. Despite intensive efforts, targeting co-factors that regulate AR and its splice variant, AR-V7 transcription, directly and efficaciously, with small molecule inhibitors has not yet been achieved. We uncovered that AR recruits the oncogene ACK1, a non-receptor tyrosine kinase, to regulate its own expression- setting up a pathological positive feedback loop in androgen deprived condition. Mechanistically, activated ACK1 modifies chromatin via phosphorylation of the histone H4 at a novel site, tyrosine 88 (pY88-H4), upstream of the AR gene at three sites AREM1-3, to promote transcription. Conversely, reversal of this pY88-H4 histone modification by treatment with a novel ACK1 inhibitor, (R)-9bMS, or overexpression of the H4Y88F mutant significantly suppressed transcription of the full length AR as well as AR-V7 splice variant, consequently downregulating expression of AR-target genes, such as PSA. Moreover, we demonstrate that WDR5/MLL2 histone-Lysine N-Methyltransferase complex, interact with the pY88-H4 epigenetic marks, deposit the transcriptionally activating H3K4 tri-methyl marks in trans, thus uncovering a novel mode of epigenetic regulation at the AR locus. Based on these extensive preliminary data, we hypothesize that inhibition of ACK1 epigenetic regulator activity that suppresses AR transcription and block production of AR splice variants will be critical to combat enzalutamide- and abiraterone-resistant CRPCs. To address this hypothesis, we will pursue the following aims: Aim 1. Assess the functional role of pY88-H4 deposition sites AREM1-3 on AR/AR-V7 transcription in CRPCs. Aim 2. Examine genome wide MLL2/WDR5/ASH2L and pY88-H4 co-association and its role in driving AR/AR-V7 expression and CRPC progression. Aim 3. Detail characterization of ACK1 inhibitor (R)-9bMS to overcome enzalutamide & abiraterone-resistance and ADME/DMPK studies.

抽象的半个多世纪以来，前列腺癌研究一直集中在雄激素受体（AR）上，它在疾病发生和发展到高度转移阶段（去势）中的作用耐药性前列腺癌（CRPC）。而 AR 拮抗剂如恩杂鲁胺或雄激素合成抑制剂阿比特龙会抑制 AR 功能活性，这些药物通常长时间无效期限，因为顽固性疾病在 2-3 年内复发。 CRPC 不仅在低或低的条件下蓬勃发展去势雄激素水平，同时也严格维持功能性 AR。因此，反雄激素抵抗已成为前列腺癌治疗中最棘手的问题之一。尽管付出了大量努力，但靶向调节 AR 及其剪接变体 AR-V7 的辅助因子尚未使用小分子抑制剂直接有效地进行转录实现了。我们发现 AR 招募癌基因 ACK1，一种非受体酪氨酸激酶，调节自身表达——在雄激素中建立病理性正反馈循环被剥夺的状况。从机制上讲，激活的 ACK1 通过磷酸化修饰染色质组蛋白 H4 位于新位点酪氨酸 88 (pY88-H4)，位于 AR 基因上游的三个位点 AREM1-3，促进转录。相反，pY88-H4 组蛋白修饰的逆转通过使用新型 ACK1 抑制剂 (R)-9bMS 或 H4Y88F 突变体的过表达进行治疗显着抑制全长 AR 以及 AR-V7 剪接变体的转录，从而下调 AR 靶基因的表达，例如 PSA。此外，我们证明 WDR5/MLL2 组蛋白-赖氨酸 N-甲基转移酶复合物与 pY88-H4表观遗传标记，将转录激活H3K4三甲基标记沉积在 trans，从而揭示了 AR 基因座的表观遗传调控的新模式。基于这些根据大量初步数据，我们假设抑制 ACK1 表观遗传调节活性抑制 AR 转录并阻止 AR 剪接变体的产生对于对抗恩杂鲁胺和阿比特龙耐药的 CRPC。为了解决这个假设，我们将追求以下目标：目标 1. 评估 AR/AR-V7 上 pY88-H4 沉积位点 AREM1-3 的功能作用 CRPC 中的转录。目标 2. 检查全基因组 MLL2/WDR5/ASH2L 和 pY88-H4 共关联及其在驱动 AR/AR-V7 表达和 CRPC 进展。目标 3. ACK1 抑制剂 (R)-9bMS 的详细表征，以克服恩杂鲁胺和阿比特龙耐药性和 ADME/DMPK 研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer.

非受体酪氨酸激酶 TNK2/ACK1 是三阴性乳腺癌的新型治疗靶点。

DOI：
发表时间：
2017-01-10
期刊：
影响因子：
0
作者：
Wu, Xinyan;Zahari, Muhammad Saddiq;Renuse, Santosh;Kelkar, Dhanashree S;Barbhuiya, Mustafa A;Rojas, Pamela L;Stearns, Vered;Gabrielson, Edward;Malla, Pavani;Sukumar, Saraswati;Mahajan, Nupam P;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh

WEE1 epigenetically modulates 5-hmC levels by pY37-H2B dependent regulation of IDH2 gene expression.

WEE1 通过 IDH2 基因表达的 pY37-H2B 依赖性调节来表观遗传调节 5-hmC 水平。

DOI：
发表时间：
2017-12-05
期刊：
影响因子：
0
作者：
Mahajan, Nupam P;Malla, Pavani;Bhagwat, Shambhavi;Sharma, Vasundhara;Sarnaik, Amod;Kim, Jongphil;Pilon;Weber, Jeffery;Mahajan, Kiran
通讯作者：
Mahajan, Kiran

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.

ACK1/TNK2 调节去势抵抗性前列腺癌中组蛋白 H4 Tyr88 磷酸化和 AR 基因表达。

DOI：
10.1016/j.ccell.2017.05.003
发表时间：
2017-06-12
期刊：
Cancer cell
影响因子：
50.3
作者：
Mahajan K;Malla P;Lawrence HR;Chen Z;Kumar-Sinha C;Malik R;Shukla S;Kim J;Coppola D;Lawrence NJ;Mahajan NP
通讯作者：
Mahajan NP