MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.
MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.
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DOI：
10.1038/s41467-021-25728-8
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发表时间：
2021-09-17
影响因子：
16.6
通讯作者：
Sos ML
中科院分区：
文献类型：
--
作者：
Brägelmann J;Lorenz C;Borchmann S;Nishii K;Wegner J;Meder L;Ostendorp J;Ast DF;Heimsoeth A;Nakasuka T;Hirabae A;Okawa S;Dammert MA;Plenker D;Klein S;Lohneis P;Gu J;Godfrey LK;Forster J;Trajkovic-Arsic M;Zillinger T;Haarmann M;Quaas A;Lennartz S;Schmiel M;D'Rozario J;Thomas ES;Li H;Schmitt CA;George J;Thomas RK;von Karstedt S;Hartmann G;Büttner R;Ullrich RT;Siveke JT;Ohashi K;Schlee M;Sos ML
激酶抑制剂抑制癌基因驱动的癌症的生长，但也加强了对治疗耐药细胞的选择，这些细胞被认为会促进患者的肿瘤复发。在这里，我们报告了对细胞和肿瘤微环境中不同基因类型的细胞和肿瘤的转录和功能基因组学分析，这些基因在激酶抑制剂治疗期间持续存在。我们发现，在经历干性和衰老相关重编程的肿瘤中，存在一种保守的MAPK/IRF1介导性炎症反应。在这些肿瘤细胞中，天然免疫传感器RIG-I通过其激动剂IVT4激活，触发干扰素和促凋亡反应，从而与伴随的激酶抑制协同作用。在人源化肺癌异种移植和同基因EGFR驱动的肺癌模型中，这些效应转化为耗尽的CD8+T细胞的减少和强劲的肿瘤缩小。总体而言，对MAPK/IRF1介导的肿瘤内重编程的机制理解可能最终延长靶向药物在基因定义的癌症患者中的疗效。激酶抑制剂被广泛用于治疗癌症，但患者经常出现耐药性。在这里，作者研究了药物持续期间的适应机制，并表明刺激先天免疫传感器RIG-I时，当与激酶抑制相结合时，会增强癌细胞的死亡。
Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition.
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DOI：
10.1056/nejmoa1502309
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hyman DM;Puzanov I;Subbiah V;Faris JE;Chau I;Blay JY;Wolf J;Raje NS;Diamond EL;Hollebecque A;Gervais R;Elez-Fernandez ME;Italiano A;Hofheinz RD;Hidalgo M;Chan E;Schuler M;Lasserre SF;Makrutzki M;Sirzen F;Veronese ML;Tabernero J;Baselga J
通讯作者：
Baselga J
影响因子：
24.8
作者：
Heidegger, Simon;Wintges, Alexander;Poeck, Hendrik
通讯作者：
Poeck, Hendrik
影响因子：
82.9
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
通讯作者：
Engelman JA
影响因子：
9.9
作者：
Das Sahu, Avinash;Lee, Joo S.;Ruppin, Eytan
通讯作者：
Ruppin, Eytan
影响因子：
11.2
作者：
Ellermeier, Jonathan;Wei, Jiwu;Schnurr, Max
通讯作者：
Schnurr, Max