The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.
The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.
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河马效应子YAP促进了对RAF和MEK靶向的癌症疗法的耐药性。
DOI：
10.1038/ng.3218
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发表时间：
2015-03
期刊：
影响因子：
30.8
通讯作者：
Bivona TG
中科院分区：
文献类型：
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作者：
Lin L;Sabnis AJ;Chan E;Olivas V;Cade L;Pazarentzos E;Asthana S;Neel D;Yan JJ;Lu X;Pham L;Wang MM;Karachaliou N;Cao MG;Manzano JL;Ramirez JL;Torres JM;Buttitta F;Rudin CM;Collisson EA;Algazi A;Robinson E;Osman I;Muñoz-Couselo E;Cortes J;Frederick DT;Cooper ZA;McMahon M;Marchetti A;Rosell R;Flaherty KT;Wargo JA;Bivona TG
对RAF和MEK靶向疗法的耐药性是一个主要的临床挑战。 RAF和MEK抑制剂最初是在BRAF基因突变的某些但并非所有患者的瞬时有效的，并且由于耐药性而在RAS基因突变的患者中无效。通过BRAF突变肿瘤细胞中的遗传筛选，我们表明河马途径效应子YAP（由YAP1编码）充当平行生存输入，以促进对RAF和MEK抑制剂治疗的抗性。在几种BRAF突变肿瘤类型中，在Ras突变肿瘤中，YAP和RAF和RAF或MEK抑制作用在综合上都是致命的。携带BRAF V600E的肿瘤中YAP的增加是对患者对RAF和MEK抑制的初始反应较差的生物标志物，并确定了我们发现的临床相关性。我们的数据将YAP确定为对RAF和MEK靶向疗法的抗药性的新机制。这些发现揭示了YAP和RAF或MEK综合抑制的合成致死性，这是增强治疗反应和患者生存的有前途的策略。
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.