河马效应器YAP可促进对RAF和MEK靶向癌症疗法的抗性。
The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.
作者信息
Lin Luping, Sabnis Amit J, Chan Elton, Olivas Victor, Cade Lindsay, Pazarentzos Evangelos, Asthana Saurabh, Neel Dana, Yan Jenny Jiacheng, Lu Xinyuan, Pham Luu, Wang Mingxue M, Karachaliou Niki, Cao Maria Gonzalez, Manzano Jose Luis, Ramirez Jose Luis, Torres Jose Miguel Sanchez, Buttitta Fiamma, Rudin Charles M, Collisson Eric A, Algazi Alain, Robinson Eric, Osman Iman, Muñoz-Couselo Eva, Cortes Javier, Frederick Dennie T, Cooper Zachary A, McMahon Martin, Marchetti Antonio, Rosell Rafael, Flaherty Keith T, Wargo Jennifer A, Bivona Trever G
机构信息
1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of California, San Francisco, San Francisco, California, USA.
出版信息
Nat Genet. 2015 Mar;47(3):250-6. doi: 10.1038/ng.3218. Epub 2015 Feb 9.
Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
对RAF和MEK靶向治疗的耐药性是一项重大临床挑战。RAF和MEK抑制剂最初对部分但并非所有携带BRAF基因突变的患者有效，但只是短暂有效，并且由于耐药性，对那些携带RAS基因突变的患者基本无效。通过对BRAF突变肿瘤细胞进行基因筛选，我们发现Hippo信号通路效应因子YAP（由YAP1编码）作为一条平行的存活信号输入，促进对RAF和MEK抑制剂治疗的耐药性。联合抑制YAP和RAF或MEK不仅在几种BRAF突变肿瘤类型中具有合成致死性，在RAS突变肿瘤中也是如此。在携带BRAF V600E的肿瘤中，YAP表达增加是患者对RAF和MEK抑制的初始反应较差的生物标志物，确立了我们研究结果的临床相关性。我们的数据确定YAP是对RAF和MEK靶向治疗产生耐药性的一种新机制。这些发现揭示了联合抑制YAP和RAF或MEK的合成致死性，是增强治疗反应和提高患者生存率的一种有前景的策略。
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