Clinical Translation of Nuclear Export Inhibitor in Metastatic Pancreatic Cancer

摘要/总结：KRAS突变是癌症中最常见的畸变之一。突变体KRAS 通过典型的RAS-RAF-MEK-ERK-RSK（RAS-RSK）信号传导驱动增殖和存活。而 KRASG 12 D，一种在癌症中发现的主要突变，仍然不可治疗，一小部分患者携带KRASG 12 C 新的靶向药物已经出现。几种KRASG 12 C抑制剂已经在预处理中进行了研究。 临床和I/II/III期研究，其中一种抑制剂sotorasib已获得FDA批准用于KRASG 12 C突变体 NSCLC患者。尽管取得了这一成功，但sotorasib或其他相关抑制剂的客观缓解率仍存在不足。 应对措施的力度不够，需要提高持久性。一些抵抗机制已经被 提出的克服对KRASG 12 C抑制剂的治疗耐药性的策略是一个激烈的话题， 调查事务所我们已经发现RAS中的蛋白质可以影响核蛋白质转运。正常 在细胞中，核物质的输出由核转运蛋白家族蛋白exportin-1/XPO 1介导， 核输出信号序列识别，并通过RAS下游效应子RanGTP促进。这 使RAN成为生长信号传导和核质转运之间的介质， 经典的RAS-RSK途径。Ran结合蛋白3（RanBP 3）被认为是通过RSK磷酸化的， 从而通过RCC 1促进RanGDP到RanGTP的转换，从而增强Ran依赖性 核质转运（图式）。这种过度活跃的核出口已被证明可以促进治疗 通过错误定位依赖性肿瘤抑制蛋白失活的耐药性。更重要的是，我们 新的研究结果表明，核输出（SINE）化合物的特异性抑制剂可以提高 KRASG 12 C抑制剂。我们假设SINE-KRASG 12 C抑制剂可能成为治疗糖尿病的独特组合。 KRASG 12 C突变型肿瘤。此外，研究这种独特的组合也将有助于揭示有形的联系， KRAS和核蛋白输出信号之间的联系。我们的具体目标是目标1。描述协同作用的特征 SINE化合物和KRASG 12 Ci之间的相互作用。目标2.显示协同作用 SINE KRASG 12 Ci之间的差异。影响：突变KRAS仍然是一个无法穿透的 堡垒和未满足的临床需求。这项工作将导致一种新的组合的进步， 两个高度寻求的癌症靶点，即KRASG 12 C和XPO 1。此外，拟议的实验还将 增强对突变KRAS与核蛋白输出之间相互作用的基本理解 途径及其治疗抵抗的后果。拟议的临床前研究将提出一个新的 和KRASG 12 C突变体驱动的耐药肿瘤的个性化治疗。

Abstract/Summary: Mutations in KRAS are among the most common aberrations in cancer. Mutant KRAS drives proliferation and survival through canonical RAS-RAF-MEK-ERK-RSK (RAS-RSK) signaling. While KRASG12D, a major mutation found in cancers remains undruggable, a smaller subset of patients carry KRASG12C mutation for which new targeted drugs have emerged. Several KRASG12C inhibitors have been studied in pre- clinical and Phase I/II/III studies and one such inhibitor sotorasib has received FDA approval for KRASG12C mutant NSCLC patients. Despite this success, the objective response rates from sotorasib or other related inhibitors has been modest and durability of response needs to be improved. A number of resistance mechanism have been proposed and strategies to overcome therapy resistance to KRASG12C inhibitors is a topic of intense investigations. We have discovered that proteins in the RAS can influence the nuclear protein transport. In normal cells, the export of nuclear cargoes is mediated by the Karyopherin family protein exportin-1/XPO1 through nuclear export signal sequence recognition and is facilitated by a RAS downstream effector RanGTP. This makes RAN a mediator between growth signaling and nucleocytoplasmic transport that can be activated through classical RAS-RSK pathway. Ran binding protein 3 (RanBP3) is recognized to be phosphorylated through RSK, resulting in the promotion of RanGDP to RanGTP conversion through RCC1 thereby enhancing Ran-dependent nucleocytoplasmic transport (schema). Such over-active nuclear export has been shown to promote therapy resistance through mislocalization dependent inactivation of tumor suppressor proteins. More significantly, our new findings show that specific inhibitors of nuclear export (SINE) compounds can enhance the efficacy of KRASG12C inhibitors. We hypothesize that SINE-KRASG12C inhibitors could become a unique combination for KRASG12C mutant tumors. Additionally, studying this unique combination will also help uncover the tangible link between KRAS and nuclear protein export signaling. Our specific aims are Aim 1. Characterize the synergy between SINE compounds and KRASG12Ci using high throughput strategies. Aim 2. Demonstrate synergy between SINE KRASG12Ci using patient derived xenograft. Impact: Mutant KRAS remains an impenetrable fortress and an unmet clinical need. This work will lead to the advancement of a novel combination that target two highly sought after cancer targets i.e. KRASG12C and XPO1. Additionally, the proposed experiments will also enhance the fundamental understanding of the interaction between mutant KRAS and nuclear protein export pathways and its consequence of therapy resistance. The proposed pre-clinical studies will bring forward a new and personalized therapy for KRASG12C mutant driven resistant tumors.