Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models.
Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models.
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DOI：
10.1158/1535-7163.mct-17-1142
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发表时间：
2018-10
影响因子：
5.7
通讯作者：
Lim KH
中科院分区：
文献类型：
--
作者：
Jiang H;Xu M;Li L;Grierson P;Dodhiawala P;Highkin M;Zhang D;Li Q;Wang-Gillam A;Lim KH
胰腺导管腺癌（PDAC）的有效治疗是一个迫切的，未满足的医疗需求。靶向KRAS（存在于>95%的PDAC中的致癌基因）是一种大力追求的策略，但在临床上仍然不成功。因此，靶向KRAS癌蛋白的关键效应子级联，特别是促有丝分裂RAF-MEK-ERK途径代表了下一个最佳策略。然而，RAF或MEK抑制剂未能在PDAC中显示出临床功效。一些研究表明，用RAF或MEK抑制剂处理的癌细胞采用多种机制来重新激活ERK信号传导。因此，ERK特异性抑制剂的开发有望有效地消除这一途径。Ulixertinib（或BVD-523）是一类ERK特异性抑制剂，在NRAS和BRAF突变晚期实体瘤的I期临床试验中显示出有前景的抗肿瘤活性，为在PDAC中测试该抑制剂提供了强有力的依据。在这项研究中，我们发现ulixertinib可有效抑制多种PDAC细胞系的体外生长，并增强吉西他滨的细胞毒性作用。此外，我们发现用ulixertinib处理的PDAC细胞通过激活HER/ErbB家族蛋白上调平行的PI 3 K-AKT通路。在体外和体内，PI 3 K或HER蛋白的同时抑制与ulixertinib协同抑制PDAC细胞生长。总体而言，我们的研究提供了在PDAC患者中测试ulixertinib与化疗或PI 3 K和HER抑制剂组合的临床前原理。
Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK pathway represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to re-activate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising anti-tumor activity in a phase 1 clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients.