Targeting PYK2 for the treatment of PDAC

胰腺导管腺癌（PDAC）在所有主要癌症中死亡率最高 是美国第三大癌症相关死亡原因，很快将成为第二大癌症相关死亡原因。 States.诊断为转移性疾病后的平均预期寿命只有三到六年 个月显然，迫切需要一种新的有效的治疗方法， 方法，但确定治疗目标，将增加PDAC患者的生存率 仍然是当前癌症研究中最大的挑战之一。由于近100%的 胰腺导管腺癌（PDAC）携带KRAS突变激活，KRAS是 理论上是PDAC治疗干预的理想候选者。但直接针对KRAS 没有成功。因此，人们对鉴定新的下游化合物非常感兴趣。 致癌KRAS信号传导的效应物，其可经受药理学干预。 PYK 2（富含脯氨酸的酪氨酸激酶2）是一种非受体细胞质酪氨酸激酶，其是 在正常胰腺中表达水平很低。我们发现PYK 2被显著诱导， 在小鼠PanIN（胰腺上皮内瘤变，PDAC的非侵入性前驱病变）中 和人PDAC组织，PYK 2升高需要KARS，并发生在 转录水平。在功能上，我们的研究结果表明，PYK 2的整体缺失，甚至 杂合缺失，显著抑制Pdx 1-Cre KRASG 12 D中PanIN的形成 小鼠模型此外，我们发现，PYK 2的shRNA敲低可以抑制肿瘤的生长。 PDAC细胞系异种移植模型，表明PYK 2是PDAC维持所需的。 从机制上讲，我们的数据显示PYK 2调节两种癌症相关途径：Wnt/p53， 连环蛋白途径和NF-κ B B途径，已知这两种途径对PDAC都很重要 起源与发展总的来说，我们的初步结果强烈表明PYK 2是一个新的 功能相关和可药物化的PDAC靶点。我们这项研究的中心假设是， PYK 2是PDAC所必需的突变KRAS信号传导的新型下游效应子 癌症发生和维持以及治疗PDAC的新的可行靶点。我们将测试我们的 通过以下具体目标的假设。目的1验证PYK 2在突变体中的作用 KRAS驱动的PDAC致癌作用。目标2将揭示PYK 2是如何在突变体中形成的 KRAS激活的信令网络。目标3将验证PYK 2抑制作为一种可行的和有效的方法。 在PDAC的临床前模型中治疗PDAC的有效方法。成功完成 目标可以证明PYK 2靶向治疗代表了一种令人兴奋的和潜在的有前途的方法， 治疗胰腺癌的新方法

Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers and is the third and soon to be the second leading cause of cancer-related deaths in the United States. The average life expectancy after diagnosis with metastatic disease is just three to six months. There obviously is an urgent and unmet need for novel effective therapeutic approaches, but identifying therapeutic targets that will increase survival rates of PDAC patients remains one of the greatest challenges in current cancer research. Since nearly 100% of pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS is theoretically ideal candidate for PDAC therapeutic intervention. But targeting KRAS directly has been unsuccessful. As a result, there is significant interest in identifying novel downstream effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention. PYK2 (proline-rich tyrosine kinase 2) is a non-receptor cytoplasmic tyrosine kinase, which is expressed at a very low level in normal pancreas. We found that PYK2 was drastically induced in mouse PanIN (pancreatic intraepithelial neoplasia, non-invasive precursor lesions of PDAC) and human PDAC tissues and that PYK2 elevation required KARS and occurred at the transcriptional level. Functionally, our results showed that whole-body deletion of PYK2, even heterozygous deletion, remarkably suppressed PanIN formation in the Pdx1-Cre KRASG12D mouse model. Further, we found that shRNA knockdown of PYK2 abrogated tumor growth in a PDAC cell line xenograft model, suggesting that PYK2 is required for PDAC maintenance. Mechanistically, our data revealed that PYK2 regulates two cancer-related pathways: the Wnt/- catenin pathway and the NF-B pathway, both pathways are known important for PDAC genesis and progression. Overall, our preliminary results strongly suggested that PYK2 is a new functionally relevant and druggable target for PDAC. Our central hypothesis of this study is that PYK2 is a novel downstream effector of mutant KRAS signaling essential for PDAC carcinogenesis and maintenance and a new actionable target for treating PDAC. We will test our hypothesis through the following Specific Aims. Aim 1 will validate the role of PYK2 in mutant KRAS-driven PDAC carcinogenesis. Aim 2 will unravel how PYK2 is hard-wired among mutant KRAS-activated signaling networks. Aim 3 will validate PYK2 inhibition as an actionable and effective approach to treating PDAC in preclinical models of PDAC. Successful completion of the aims could prove that PYK2-targeted therapy represents an exciting and potentially promising new approach to treating pancreatic cancer.