Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments. Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS -driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a two-dimensional monolayer culture system as well as three-dimensional spheroid culture system, we conducted a screen of a large panel of anticancer agents and found that MAP2K (MEK) inhibitors were most effective in targeting PDAC spheroids in comparison with monolayer cultures. Combination treatment with an MEK inhibitor and the multikinase inhibitor ponatinib was effective in targeting pancreatic cancer cells both in monolayer and spheroids by effectively blocking signaling via the PDGFRα and MEK kinases, while also preventing the activation of STAT3- and S6-mediated compensatory feedback loops in cancer cells. Furthermore, using xenograft models, we demonstrate that cotreatment with a MEK inhibitor and ponatinib causes significant tumor regression. PDAC patient samples also provided evidence of increased STAT3 activation in PDAC tumors and MAPK1 (ERK) activation in liver metastases, implicating STAT3 and ERK as key drivers in primary tumors and metastases, respectively. These results reveal a combination drug treatment strategy that may be effective in pancreatic cancer. Mol Cancer Ther; 16(9); 1729–38. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 1727][1] [1]: /lookup/volpage/16/1727?iss=9

中文翻译：

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MEK和PDGFR / STAT3途径的共同靶向治疗胰腺导管腺癌。

胰腺导管腺癌（PDAC）是最致命的人类疾病之一，对可用的药物治疗仍然具有很大的抵抗力。已知致癌驱动因子的靶向不足以及补偿性反馈回路的激活以及无法防止转移性扩散，导致该疾病的预后不良。在大多数胰腺癌中，由KRAS驱动的MEK途径被突变激活，并且是治疗的重要靶标。使用二维单层培养系统和三维球体培养系统，我们对一大批抗癌药进行了筛选，发现与单层培养相比，MAP2K（MEK）抑制剂在靶向PDAC球体方面最有效。MEK抑制剂和多激酶抑制剂ponatinib的联合治疗可有效阻断PDGFRα和MEK激酶的信号传导，从而有效靶向单层和球状胰腺癌细胞，同时还可防止STAT3和S6介导的补偿性反馈回路的激活。癌细胞。此外，使用异种移植模型，我们证明与MEK抑制剂和ponatinib共同治疗可导致明显的肿瘤消退。PDAC患者样品还提供了PDAC肿瘤中STAT3激活增加和肝转移中MAPK1（ERK）激活增加的证据，分别暗示STAT3和ERK是原发性肿瘤和转移的关键驱动因素。这些结果揭示了在胰腺癌中可能有效的联合药物治疗策略。分子癌疗法；16（9）; 1729–38。©2017 AACR。本文在本期要点[p。1727] [1] [1]：/ lookup / volpage / 16/1727？iss = 9