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

描述（由申请人提供）：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）的最可行方向，大多数研究都集中在Raf-MEK-ERK丝裂原活化蛋白激酶（MAPK）级联上。目前有18种Raf或MEK抑制剂正在进行I-III期临床评估。然而，在抑制剂阻断下游恢复ERK激活或激活平行活动以减少ERK依赖性的信号重编程机制严重限制了它们的抗肿瘤活性。SCH772984是最近开发的一种新型、高选择性atp竞争和变弹性ERK1和ERK2抑制剂，目前正处于RAS或BRAF突变型癌症的Ib期临床评估。我们建议研究确定克服ERK抑制和驱动ERK异构体差异的信号机制，以推进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细胞系锚定依赖性和非依赖性生长方面比MEK抑制剂更有效。然而，PDAC的一个子集显示出对SCH772984的从头（初级）抗性。我们还发现，高剂量SCH772984处理敏感的PDAC品系会导致获得性（继发性）耐药亚群的生长。我们将使用可药物化的基因组siRNA筛选来鉴定控制SCH772984新生和获得性PDAC耐药的基因。我们假设这些研究将确定联合抑制剂方法，协同增强ERK抑制剂的抗肿瘤活性。其次，令人惊讶的是，尽管ERK1和ERK2具有高序列和生化特性，但我们确定ERK1和ERK2在PDAC生长中表现出不同的、不重叠的基本功能。全基因组磷酸化蛋白质组学方法将用于鉴定PDAC生长所必需的ERK亚型特异性底物。除了描述由ERK激活驱动的新的信号机制外，这些研究可能为同种异构体选择性抗ERK治疗策略确定方向。我们应用创新策略研究erk依赖性PDAC的增长是高风险的；但鉴于ERK在PDAC生长中的关键作用，我们的研究结果在PDAC治疗方面具有很高的突破潜力。

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.