Griffin Merope, Scotto Daniele, Josephs Debra H, Mele Silvia, Crescioli Silvia, Bax Heather J, Pellizzari Giulia, Wynne Matthew D, Nakamura Mano, Hoffmann Ricarda M, Ilieva Kristina M, Cheung Anthony, Spicer James F, Papa Sophie, Lacy Katie E, Karagiannis Sophia N
St John's Institute of Dermatology, Genetics and Molecular Medicine, King's College London, Guy's Hospital, Tower Wing, London, UK.
Research Oncology, School of Cancer Sciences, King's College London, Guy's Hospital, Bermondsey Wing, London, UK.
Oncotarget. 2017 Aug 3;8(44):78174-78192. doi: 10.18632/oncotarget.19836. eCollection 2017 Sep 29.
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.
编码丝氨酸/苏氨酸蛋白激酶BRAF的基因发生突变，以及约50%的恶性黑色素瘤中丝裂原活化蛋白激酶（MAPK）途径的组成性激活，促使了靶向途径抑制剂药物的研发并获得监管批准。一部分患者对BRAF抑制剂具有内在抗性，并且大多数最初有反应的患者在数月内就会产生抗性。在本综述中，我们讨论了途径抑制剂及其抗性机制，并着重介绍了通过将作用方式不同的药物联合使用（包括与检查点抑制剂抗体联合）来提高临床疗效的诸多努力。我们讨论了基于增强免疫反应或克服肿瘤相关免疫逃逸机制的联合策略的优点。对作用机制、抗性途径及其对宿主-肿瘤关系影响的新见解，将为优化联合治疗方案的设计提供依据，从而改善目前无法从近期治疗突破中获益的患者的治疗效果。
