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

• 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
• 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

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， 它在疾病的启动和向高度转移阶段的发展中的作用 抗性前列腺癌（CRPC）。而AR拮抗剂（例如enzalutamide或androgen-） 合成抑制剂abiraterone抑制AR功能活性，通常是无效的长时间 术语，因为顽固性疾病在2 - 3年内复发。 CRPC不仅在低或 恒定的雄激素水平，但也仔细维持功能性AR。因此，反 - 雄激素抵抗已成为前列腺癌疗法中最烦人的问题之一。 尽管进行了大量努力，但针对调节AR的共同因素及其剪接变体AR-V7 转录，直接和有效，尚未使用小分子抑制剂 成就了。我们发现AR招募了一种非受体酪氨酸激酶Oncogene Ack1 调节自己的表达 - 在雄激素中建立病理阳性反馈回路 剥夺状态。从机械上讲，活化的ACK1通过磷酸化修饰染色质 在三个地点的AR基因上游的新型酪氨酸88（PY88-H4）的新型酪氨酸88（PY88-H4）的组蛋白H4 AREM1-3，以促进转录。相反，这种PY88-H4组蛋白修饰的逆转 通过使用新型ACK1抑制剂（R）-9BMS或H4Y88F突变体的过表达来处理 明显抑制全长AR以及AR-V7剪接变体的转录， 因此，下调了Ar-Target基因的表达，例如PSA。而且，我们 证明WDR5/MLL2组蛋白赖氨酸N-甲基转移酶复合酶复合物与 PY88-H4表观遗传标记，将转录激活的H3K4三甲基标记沉积在 跨性别，从而发现了一种新型的表观遗传调节模式。基于这些 广泛的初步数据，我们假设抑制ACK1表观遗传调节剂活性 这抑制AR转录和AR剪接变体的阻断产生对 战斗Enzalutamide-和阿比罗酮的CRPC。为了解决这一假设，我们将 追求以下目的： AIM 1。评估PY88-H4沉积位点AREM1-3在AR/AR-V7上的功能作用 CRPC中的转录。 AIM 2。检查基因组宽MLL2/WDR5/ASH2L和PY88-H4共同关联及其在 驱动AR/AR-V7表达和CRPC进展。 目标3。详细表征ACK1抑制剂（R）-9BMS以克服enzalutamide＆ 阿比罗酮的抗性和ADME/DMPK研究。

项目成果

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

• 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

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

• DOI: 10.18632/oncotarget.13579
• 发表时间: 2017-01-10
• 期刊: Oncotarget
• 作者: Wu X;Zahari MS;Renuse S;Kelkar DS;Barbhuiya MA;Rojas PL;Stearns V;Gabrielson E;Malla P;Sukumar S;Mahajan NP;Pandey A
• 通讯作者: Pandey A