Robinson James P, Rebecca Vito W, Kircher David A, Silvis Mark R, Smalley Inna, Gibney Geoffrey T, Lastwika Kristin J, Chen Guo, Davies Michael A, Grossman Douglas, Smalley Keiran S M, Holmen Sheri L, VanBrocklin Matthew W
aThe Hormel Institute, University of Minnesota, Austin, Minnesota bDepartment of Medicine and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Departments of cOncological Sciences dSurgery eDermatology fHuntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah gDepartment of Tumor Biology, Tumor Biology hDepartment of Cutaneous Oncology, Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida iDepartment of Medicine, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital jDepartment of Global Health, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, DC kDepartment of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Melanoma Res. 2017 Dec;27(6):545-557. doi: 10.1097/CMR.0000000000000403.
Targeted therapies have revolutionized cancer care, but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice, but 40% of tumors recurred. Analysis of resistant tumors showed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells showed enhanced efficacy of cytotoxicity with combined RTK and mitogen-activated protein kinase kinase inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.
靶向治疗彻底改变了癌症治疗方式，但耐药性的产生仍是临床上的一项挑战。为了确定联合治疗策略的合理靶点，我们使用了一种已建立的黑色素瘤小鼠模型，并在基因抑制NRAS表达后筛选出耐药肿瘤。所有小鼠的肿瘤均完全消退，但40%的肿瘤复发。对耐药肿瘤的分析表明，最常见的耐药机制是受体酪氨酸激酶（RTK）的过表达和激活。有趣的是，最常过表达的RTK是Met，在此背景下抑制Met可克服NRAS耐药性。对NRAS突变的人黑色素瘤细胞的分析表明，联合抑制RTK和丝裂原活化蛋白激酶激酶可增强细胞毒性疗效。在本研究中，我们确立了适应性RTK信号传导在NRAS突变黑色素瘤逃避RAS抑制中的重要性，并为此背景下联合阻断RAS和RTK信号传导提供了理论依据。
