Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.
Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.
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DOI：
10.1016/j.ccell.2018.08.009
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发表时间：
2018-09-10
期刊：
影响因子：
50.3
通讯作者：
Barbie DA
中科院分区：
文献类型：
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作者：
Kitajima S;Asahina H;Chen T;Guo S;Quiceno LG;Cavanaugh JD;Merlino AA;Tange S;Terai H;Kim JW;Wang X;Zhou S;Xu M;Wang S;Zhu Z;Thai TC;Takahashi C;Wang Y;Neve R;Stinson S;Tamayo P;Watanabe H;Kirschmeier PT;Wong KK;Barbie DA
尽管进行了广泛的努力，致癌KRAS仍然对靶向治疗具有抗性。在KRAS驱动的基因工程小鼠模型（GEMM）中，下游RAL-TBK 1和MEK联合抑制仅诱导短暂的肺肿瘤缩小。采用灵敏的KRAS;在LKB 1（KL）突变背景下，我们鉴定了YAP 1上调和治疗诱导的分泌组作为获得性耐药的介质。该程序是可逆的，与H3 K27启动子乙酰化相关，并被BET抑制抑制，使抗性KL细胞对TBK 1/MEK抑制重新敏感。组成型YAP 1信号促进KRAS; TP 53（KP）突变型肺癌的内在耐药性因此，用BET抑制剂JQ 1间歇处理克服了KL和KP GEMM中对组合途径抑制的抗性。使用有效的和选择性的TBK 1和BET抑制剂，我们进一步开发了一种有效的治疗策略，具有潜在的临床应用价值。Kitajima等鉴定了BET调节的YAP 1上调分别作为KRAS; LKB 1和KRAS; TP 53突变型肺癌细胞中获得性和内在抗性的介导物，以组合TBK 1和MEK抑制，并显示间歇性BET抑制克服了这种抗性。
Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic. Kitajima et al. identify BET-regulated YAP1 upregulation as a mediator of acquired and intrinsic resistance in KRAS;LKB1 and KRAS;TP53 mutant lung cancer cells, respectively, to combined TBK1 and MEK inhibition and show that intermittent BET inhibition overcomes this resistance.
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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。
影响因子：
30.8
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
通讯作者：
Bivona TG
影响因子：
64.8
作者：
Chen, Zhao;Cheng, Katherine;Walton, Zandra;Wang, Yuchuan;Ebi, Hiromichi;Shimamura, Takeshi;Liu, Yan;Tupper, Tanya;Ouyang, Jing;Li, Jie;Gao, Peng;Woo, Michele S.;Xu, Chunxiao;Yanagita, Masahiko;Altabef, Abigail;Wang, Shumei;Lee, Charles;Nakada, Yuji;Pena, Christopher G.;Sun, Yanping;Franchetti, Yoko;Yao, Catherine;Saur, Amy;Cameron, Michael D.;Nishino, Mizuki;Hayes, D. Neil;Wilkerson, Matthew D.;Roberts, Patrick J.;Lee, Carrie B.;Bardeesy, Nabeel;Butaney, Mohit;Chirieac, Lucian R.;Costa, Daniel B.;Jackman, David;Sharpless, Norman E.;Castrillon, Diego H.;Demetri, George D.;Jaenne, Pasi A.;Pandolfi, Pier Paolo;Cantley, Lewis C.;Kung, Andrew L.;Engelman, Jeffrey A.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
64.5
作者：
Rosenbluh J;Nijhawan D;Cox AG;Li X;Neal JT;Schafer EJ;Zack TI;Wang X;Tsherniak A;Schinzel AC;Shao DD;Schumacher SE;Weir BA;Vazquez F;Cowley GS;Root DE;Mesirov JP;Beroukhim R;Kuo CJ;Goessling W;Hahn WC
通讯作者：
Hahn WC
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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