Broussard Lindsey, Howland Amanda, Ryu Sunhyo, Song Kyungsup, Norris David, Armstrong Cheryl A, Song Peter I
Department of Dermatology, University of Colorado Denver School of Medicine, Aurora, CO, USA.
Department of Internal Medicine, University of Colorado Denver School of Medicine, Aurora, CO, USA.
Chonnam Med J. 2018 Sep;54(3):135-142. doi: 10.4068/cmj.2018.54.3.135. Epub 2018 Sep 27.
Over recent years, several new molecular and immunogenic therapeutic approaches to melanoma treatment have been approved and implemented in clinical practice. Mechanisms of resistance to these new therapies have become a major problem. Mutation-specific pharmacotherapy can result in simultaneous emergence of resistant clones at many separate body sites despite an initially positive therapeutic response. Additionally, treatments aimed at inducing apoptosis are subject to resistance due to escape through other known mechanisms of regulated cell death (RCD). In this review, we discuss the complexity in pharmacological manipulation of melanoma with c-Kit, BRAF, MEK, and/or mTOR mutant cell lines. This study also addresses melanoma evasion of cell death through modalities of RCD such as apoptosis, autophagy, and necroptosis. This study also examines new combination therapies which have been approved to target both cell cycle dysregulation and cell death pathways. Lastly, we recognize the importance of immunomodulation though manipulation of the body's natural killing mechanisms with CTLA4, PD1, and CSF1 inhibition. As we begin to recognize tumor cell activation of alternate pathways, evasion of programmed cell death, and manipulation of the tumor microenvironment, it is increasingly important to grasp the complexity of personalized therapy in melanoma treatment.
近年来，几种用于黑色素瘤治疗的新分子和免疫原性治疗方法已获批准并应用于临床实践。对这些新疗法的耐药机制已成为一个主要问题。尽管最初治疗反应呈阳性，但突变特异性药物治疗仍可能导致在许多不同身体部位同时出现耐药克隆。此外，旨在诱导细胞凋亡的治疗会因通过其他已知的程序性细胞死亡（RCD）机制逃逸而产生耐药性。在本综述中，我们讨论了用c-Kit、BRAF、MEK和/或mTOR突变细胞系对黑色素瘤进行药理操作的复杂性。本研究还探讨了黑色素瘤通过凋亡、自噬和坏死性凋亡等RCD方式逃避细胞死亡的情况。本研究还考察了已获批准的针对细胞周期失调和细胞死亡途径的新联合疗法。最后，我们认识到通过抑制CTLA4、PD1和CSF1来操纵机体自然杀伤机制进行免疫调节的重要性。随着我们开始认识到肿瘤细胞对替代途径的激活、对程序性细胞死亡的逃避以及对肿瘤微环境的操纵，掌握黑色素瘤治疗中个性化治疗的复杂性变得越来越重要。
