ERK inhibitor resistance and ERK isoform-dependent growth in pancreatic cancer

描述(申请人提供)：RAS效应信号的抑制剂被认为是成功开发有效的抗RAS疗法治疗胰腺导管腺癌(PDAC)最可行的方向，最主要的努力集中在Raf-MEK-ERK丝裂原活化蛋白激酶(MAPK)级联。18种Raf或MEK抑制剂目前正在进行I-III期临床评估。然而，恢复抑制物下游ERK激活的信号重编程机制，或激活平行活动以减少对ERK的依赖，严重限制了它们的抗肿瘤活性。SCH772984是最近开发的一种新型的、高度选择性的ATP竞争性和变构ERK1和ERK2抑制剂，目前正在进行针对RAS或BRAF突变癌症的Ib期临床评估。我们建议进行研究，以确定克服ERK抑制和驱动ERK异构体差异的信号机制，长期目标是推动SCH772984和其他ERK抑制剂的临床开发。首先，我们的初步研究发现，SCH772984在阻断PDAC细胞系锚定依赖和非独立生长方面比MEK抑制更有效。然而，部分PDAC品系表现出对SCH772984的从头(初级)抗性。我们还发现，高剂量的SCH772984处理敏感的PDAC品系导致了具有获得性(次级)抗性的亚群的生长。我们将应用可药物基因组siRNA筛选来识别控制从头开始与获得性PDAC对SCH772984耐药性的基因。我们假设这些研究将确定协同增强ERK抑制剂抗肿瘤活性的联合抑制剂方法。第二，令人惊讶的是，尽管ERK1和ERK2具有很高的序列和生化同一性，但我们确定ERK1和ERK2在PDAC生长中显示出不同的、不重叠的基本功能。一种全基因组的磷酸蛋白质组学方法将被应用于鉴定对PDAC生长至关重要的ERK异构体特异性底物。除了描绘由ERK激活驱动的新的信号机制外，这些研究还可能确定异构体选择性抗ERK治疗策略的方向。我们应用创新策略来研究依赖ERK的PDAC生长是高风险的；但由于ERK在PDAC生长中的关键作用，我们的发现具有在PDAC治疗方面取得突破的高增长潜力。

DESCRIPTION (provided by applicant): Inhibitors of Ras effector signaling are considered the most viable direction for successful development of effective anti-Ras therapies for the treatment of pancreatic ductal adenocarcinoma (PDAC), with most efforts focused on the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. Eighteen Raf or MEK inhibitors are currently under Phase I-III clinical evaluation. However, signaling reprogramming mechanisms that restore ERK activation downstream of the inhibitor block, or that activate parallel activities to reduce ERK dependency, have severely limited their anti-tumor activities. SCH772984 is a recently developed novel, highly selective ATP-competitive and allosteric ERK1 and ERK2 inhibitor that is currently under Phase Ib clinical evaluation for RAS or BRAF mutant cancers. We propose studies to define signaling mechanisms that overcome ERK inhibition and drive ERK isoform differences, with the long-term goal to advance the clinical development of SCH772984 and other ERK inhibitors. First, our preliminary studies found SCH772984 more effective than MEK inhibition for blocking PDAC cell line anchorage-dependent and -independent growth. However, a subset of PDAC lines showed de novo (primary) resistance to SCH772984. We have also found that high-dose SCH772984 treatment of sensitive PDAC lines resulted in the outgrowth of subpopulations with acquired (secondary) resistance. We will apply druggable genome siRNA screens to identify genes that control de novo versus acquired PDAC resistance to SCH772984. We hypothesize that these studies will identify combination inhibitor approaches that synergistically enhance the anti-tumor activity of ERK inhibitors. Second, surprisingly, despite their high sequence and biochemical identity, we determined that ERK1 and ERK2 display distinct, non-overlapping essential functions in PDAC growth. A genome-wide phosphoproteomics approach will be applied to identify ERK isoform-specific substrates essential for PDAC growth. In addition to delineating novel signaling mechanisms driven by ERK activation, these studies may identify directions for isoform-selective anti-ERK therapeutic strategies. Our application of innovative strategies to study ERK-dependent PDAC growth are high risk; but with the critical importance of ERK in PDAC growth, our findings have high-gain potential for a breakthrough in PDAC therapy.