Kuracha Murali R, Thomas Peter, Loggie Brian W, Govindarajan Venkatesh
Department of Surgery, Creighton University, Omaha, Nebraska, United States of America.
Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, United States of America.
PLoS One. 2017 Jun 22;12(6):e0179510. doi: 10.1371/journal.pone.0179510. eCollection 2017.
Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence ('addiction') of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei.
黏液性结直肠癌（MCA）在临床和形态学上与非黏液性结直肠癌（CRC）不同，表现出独特的基因改变谱（KRAS突变率较高、p53较低、MUC2较高），具有更具侵袭性的行为（更易发生腹膜播散和淋巴结受累），并且对化疗反应较差，治疗选择有限。在此，我们报告了联合靶向两条KRAS介导的平行途径在体外和体内减少MUC2产生和黏液性肿瘤生长方面的有效性。通过敲低突变型KRAS，我们发现，突变型KRAS（a）在体外是MUC2产生所必需的，并且（b）协同激活PI3K/AKT和MEK/ERK途径以维持MCA细胞中MUC2的表达。这些结果确定了致癌性KRAS在黏液性癌中一个新的且以前未描述的作用。MCA细胞对MEK抑制敏感，表明KRAS突变的MCA细胞对MEK驱动途径的过度激活存在细胞依赖性（“成瘾性”）。有趣的是，MCA细胞虽然最初敏感，但后来对PI3K单药抑制产生耐药性。我们的研究表明，这种耐药性涉及通过解除RTK抑制和MEK-ERK反弹激活介导的信号通路的动态重新布线。然而，这种耐药性可以通过同时靶向PI3K和MEK来克服。因此，我们的研究为不仅针对KRAS突变的MCA而且针对其他相关的过度产生MUC2且KRAS突变率高的黏液性肿瘤（如腹膜假黏液瘤）的MEK和PI3K靶向联合治疗提供了合理依据。
