Fujita-Sato Saori, Galeas Jacqueline, Truitt Morgan, Pitt Cameron, Urisman Anatoly, Bandyopadhyay Sourav, Ruggero Davide, McCormick Frank
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Cancer Res. 2015 Jul 15;75(14):2851-62. doi: 10.1158/0008-5472.CAN-14-1623. Epub 2015 May 14.
Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients.
致癌性K-Ras突变在包括胰腺癌和肺癌在内的多种癌症中频繁发生。具有K-Ras突变的肿瘤对化疗药物以及分子靶向药物具有抗性。尽管目前正在进行大量研究以寻找治疗这些肿瘤的有效方法，但对于K-Ras突变型癌症患者仍没有有效的治疗方法。在此我们报告，与单层培养条件相比，K-Ras突变型癌症在非锚定依赖培养条件下对K-Ras的依赖性更强。在试图确定导致非锚定依赖培养条件下K-Ras依赖性的机制时，我们发现Met参与了K-Ras依赖性的非锚定依赖细胞生长。即使在Met未扩增的细胞中，Met信号通路也会增强并在非锚定依赖生长中发挥不可或缺的作用。事实上，在非锚定依赖生长条件下Met表达升高，并且由K-Ras以丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）依赖的方式调控。值得注意的是，尽管在非锚定依赖生长过程中mRNA翻译整体下调，但我们发现在这些条件下Met mRNA翻译会特异性增强。重要的是，活性Met突变体的异位表达挽救了K-Ras缺失导致的生长抑制，表明K-Ras介导的Met表达在非锚定依赖条件下驱动“K-Ras成瘾”。我们的结果表明，Met表达和信号增强对于K-Ras突变型癌细胞的非锚定依赖生长至关重要，并提示Met的药理抑制剂可能对K-Ras突变型肿瘤患者有效。
