BRAF inhibitors: resistance and the promise of combination treatments for melanoma.
BRAF inhibitors: resistance and the promise of combination treatments for melanoma.
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DOI：
10.18632/oncotarget.19836
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Karagiannis SN
中科院分区：
文献类型：
--
作者：
Griffin M;Scotto D;Josephs DH;Mele S;Crescioli S;Bax HJ;Pellizzari G;Wynne MD;Nakamura M;Hoffmann RM;Ilieva KM;Cheung A;Spicer JF;Papa S;Lacy KE;Karagiannis SN
在大约 50% 的恶性黑色素瘤中，对编码丝氨酸/苏氨酸蛋白激酶 BRAF 的基因突变和丝裂原激活蛋白激酶 (MAPK) 通路的组成性激活进行了鉴定，从而导致了靶向通路抑制剂药物的开发和监管批准。一部分患者对 BRAF 抑制剂具有内在耐药性，大多数最初有反应的患者会在几个月内获得耐药性。在这篇综述中，我们讨论了途径抑制剂及其耐药机制，并重点关注通过将具有不同作用模式的药物（包括与检查点抑制剂抗体的组合）相结合来提高临床效益的众多努力。我们讨论基于增强免疫反应或克服肿瘤相关免疫逃逸机制的组合策略的优点。对作用机制、耐药途径及其对宿主-肿瘤关系影响的新见解将为设计最佳联合疗法提供信息，以改善目前未从近期治疗突破中受益的患者的治疗结果。
Identification of mutations in the gene encoding the serine/threonine-protein kinase, BRAF, and constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in around 50% of malignant melanomas have led to the development and regulatory approval of targeted pathway inhibitor drugs. A proportion of patients are intrinsically resistant to BRAF inhibitors, and most patients who initially respond, acquire resistance within months. In this review, we discuss pathway inhibitors and their mechanisms of resistance, and we focus on numerous efforts to improve clinical benefits through combining agents with disparate modes of action, including combinations with checkpoint inhibitor antibodies. We discuss the merits of combination strategies based on enhancing immune responses or overcoming tumor-associated immune escape mechanisms. Emerging insights into mechanisms of action, resistance pathways and their impact on host-tumor relationships will inform the design of optimal combinations therapies to improve outcomes for patients who currently do not benefit from recent treatment breakthroughs.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
11.2
作者：
Ho PC;Meeth KM;Tsui YC;Srivastava B;Bosenberg MW;Kaech SM
通讯作者：
Kaech SM
影响因子：
6.5
作者：
Gowrishankar, Kavitha;Snoyman, Stephanie;Rizos, Helen
通讯作者：
Rizos, Helen
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS