Targeting PYK2 for the treatment of PDAC

胰腺导管腺癌是所有主要癌症中死亡率最高的。 它是美国癌症相关死亡的第三大原因，也将很快成为第二大原因 各州。被诊断出患有转移性疾病后的平均预期寿命只有3到6岁。 月份。显然，对新的有效治疗方法的迫切需求尚未得到满足。 方法，但确定治疗靶点，将提高PDAC患者的存活率 仍然是当前癌症研究中最大的挑战之一。因为几乎100%的 胰腺导管腺癌(PDAC)携带KRAS的突变激活，KRAS是 理论上是PDAC治疗干预的理想候选者。但直接以KRAS为目标 一直不成功。因此，人们对识别新的下游有很大的兴趣 可能受药物干预的致癌KRAS信号的效应者。 PYK2(富含脯氨酸的酪氨酸激酶2)是一种非受体胞浆酪氨酸激酶，是一种非受体酪氨酸激酶。 在正常胰腺中的表达水平很低。我们发现PYK2被强烈地诱导 在小鼠Panin(胰腺上皮内瘤变，PDAC的非侵袭性前体病变)中 和人的PDAC组织，而PYK2的升高需要Kars，并发生在 转录水平。在功能上，我们的结果表明，PYK2的全身缺失，甚至 Pdx1-Cre KrasG12D杂合性缺失显著抑制Panin的形成 老鼠模型。此外，我们发现PYK2的shRNA敲除抑制了肿瘤的生长。 PDAC细胞系异种移植模型，提示PYK2对PDAC的维持是必需的。 从机制上讲，我们的数据显示PYK2调节两条与癌症相关的通路：Wnt/- 连环蛋白途径和核因子-B途径，这两个途径都是已知的重要的PDAC 《创世纪与进化》。总体而言，我们的初步结果强烈表明，PYK2是一种新的 PDAC的功能相关和可用药靶点。我们对这项研究的中心假设是 PYK2是PDAC必需的突变KRAS信号的新下游效应器 肿瘤的发生和维持以及治疗PDAC的新的操作靶点。我们将测试我们的 通过以下具体目标提出假设。AIM 1将验证PYK2在突变中的作用 KRAS驱动的PDAC致癌作用。Aim 2将揭开PYK2是如何在突变体中固定的 KRAS激活的信令网络。AIM 3将验证PYK2抑制是一种可行的 临床前PDAC模型治疗PDAC的有效途径。圆满完成 AIMS可以证明PYK2靶向治疗代表了一种令人兴奋的和潜在的前景 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.