RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis

RIPK2/MKK7/c-Myc信号通路作为前列腺癌转移治疗靶点的研究 摘要：尽管前列腺癌(PC)的治疗取得了进展，但远处转移仍然是主要原因。 这对PC的发病率和死亡率造成了巨大的社会和经济负担。三个近期的III期临床 试验(即斯巴达、Prosper和Aramis)明确地证明，预防或延迟PC 转移提供了强大的临床益处，将中位总生存期延长了10-14个月。留住 增强动力，进一步提高PC的无转移存活率(总体存活率的有力替代指标) 患者，迫切需要在PC转移中寻找新的可用药靶点，并描绘他们的 行动机制(MOAS)。通过对三个临床组学数据库的综合分析，我们发现 受体相互作用蛋白激酶2(RIPK2)是PC转移的首选药物靶点。RIPK2是 65%致死性转移性去势抵抗PC的扩增/增强与其mRNA的过度表达相关 病情进展，预后差。RIPK2基因敲除(RIPK2-KO)或用有效的RIPK2治疗 抑制剂(如FDA批准的波纳替尼)显著抑制PC细胞的侵袭和集落形成，但 在体外不增殖，体内转移减少高达92%。机械上的，独特的 从典型的NOD/RIPK2/NF-κB途径来看，RIPK2强烈地调节c-Myc(A)的稳定性和活性 PC转移的驱动力)，主要是通过结合和激活MKK7，我们发现它是一种新的直接c-Myc- S62激酶。这种非规范的RIPK2/MKK7/c-Myc信号通路可以被RIPK2-KO有效地灭活 或波那替尼，因此是治疗PC转移的非常有前景的药物靶点。在这里，我们的总体目标是提供一个 通过检验一个中心假设：RIPK2/MKK7/c-Myc信号转导是 与患者的PC进展、转移和预后不良有关，并对RIPK2依赖至关重要 PC转移及其抑制是Ponatinib抑制PC的主要(尽管不是唯一的)MOA 转移。PI组建了一支出色的多学科团队，以追求三个截然不同但相互关联的 具体目标：1)评估RIPK2/MKK7/c-Myc信号转导的临床相关性和分子基础， 2)确定RIPK2-KO是否主要通过失活MKK7/c-Myc信号途径抑制PC转移 Ponatinib是否主要通过失活RIPK2/MKK7/c来抑制PC转移。 MYC信号转导，并确定Ponatinib抑制PC转移的RIPK2非依赖性MOAS。如果成功， 这项拟议的研究将揭示PC转移的一个新的致命弱点，并揭示RIPK2的主要MOAS- KO和Ponatinib对PC转移的抑制作用他们将提供有价值的临床前数据来指导 开发一项重新调整用途的临床试验，以显著改善患者的临床结果 转移性PC的风险。鉴于RIPK2和MYC共扩增/获得在多发性癌症中的高患病率 类型，拟议的研究发现的MOAS将具有超越PC领域的临床意义。

RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis ABSTRACT: Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality of PC, imposing significant social and economic burdens. Three recent phase III clinical trials (i.e., SPARTAN, PROSPER, and ARAMIS) unequivocally demonstrated that preventing or delaying PC metastasis provides strong clinical benefits, prolonging the median overall survival by 10-14 months. To keep up the momentum and further improve the metastasis-free survival (a strong surrogate of overall survival) of PC patients, there is an urgent unmet need to identify novel druggable targets in PC metastasis and delineate their mechanisms of action (MoAs). Through an integrated analysis of three clinical omics databases, we identified receptor-interacting protein kinase 2 (RIPK2) as a top druggable target candidate for PC metastasis. RIPK2 is amplified/gained in 65% of lethal metastatic castration-resistant PC and its mRNA overexpression is associated with disease progression and poor prognosis. RIPK2 knockout (RIPK2-KO) or treatment with a potent RIPK2 inhibitor (e.g., the FDA-approved ponatinib) significantly suppressed PC cell invasion and colony formation but not proliferation in vitro and reduced the metastasis of 22Rv1 cells by up to 92% in vivo. Mechanistically, distinct from the canonical NOD/RIPK2/NF-κB pathway, RIPK2 strongly regulates the stability and activity of c-Myc (a driver of PC metastasis), largely by binding and activating MKK7, which we identified as a novel direct c-Myc- S62 kinase. This noncanonical RIPK2/MKK7/c-Myc signaling pathway can be potently inactivated by RIPK2-KO or ponatinib and thus is a very promising drug target in PC metastasis. Here, our overall goal is to provide a strong scientific rationale for a clinical trial by testing a central hypothesis: RIPK2/MKK7/c-Myc signaling is associated with PC progression, metastasis, and poor prognosis in patients and is critical for RIPK2-dependent PC metastasis, and its inhibition is the primary (albeit not the only) MoA of ponatinib in suppressing PC metastasis. The PI has assembled an outstanding multi-disciplinary team to pursue three distinct but interrelated specific aims: 1) assess the clinical correlations and refine the molecular basis of RIPK2/MKK7/c-Myc signaling, 2) determine whether RIPK2-KO inhibits PC metastasis primarily by inactivating the MKK7/c-Myc signaling pathway, and 3) determine whether ponatinib impairs PC metastasis primarily by inactivating RIPK2/MKK7/c- Myc signaling and define RIPK2-independent MoAs of ponatinib in suppressing PC metastasis. If successful, the proposed studies will expose a novel Achilles’ heel for PC metastasis and reveal the major MoAs of RIPK2- KO and ponatinib in suppressing PC metastasis. They will provide valuable preclinical data to guide the development of a clinical trial repurposing ponatinib to substantially improve the clinical outcomes of patients at risk for metastatic PC. Given the high prevalence of RIPK2 and MYC co-amplification/gain in multiple cancer types, the MoAs uncovered by the proposed studies will have clinical implications beyond the PC space.