Nigam Sankalp, Enshaie Elliot, Smith Jacob, Rai Vikrant
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
Department of Translational Research, Western University of Health Sciences, Pomona, CA, USA.
Chin Clin Oncol. 2025 Jun;14(3):34. doi: 10.21037/cco-25-9.
Melanoma is one of the most common types of skin cancer and is the most lethal type of skin cancer presently. Despite the presence of various drugs for the treatment of melanomas, increasing resistance to the existing treatment is a major concern. Due to the involvement of complex mechanisms including genetic mutations, the presence of neoantigens, tumor microenvironment, and cellular plasticity, the tumor cell develops the ability to evade the effects of current therapies including targeted drugs and immunotherapy limiting the treatment efficacy. This leads to difficulties in achieving long-term control in patients with advanced melanoma. It is important to understand the molecular mechanisms underlying chemoresistance to overcome this resistance and develop potential therapeutic strategies. In this article, we will discuss the most common drugs used to fight skin cancer and their mechanisms of fighting cancer, followed by a discussion of intrinsic resistance and extrinsic resistance. We will address molecular mechanisms of chemoresistance including the alteration in apoptosis and lipid metabolism, the role of tumor microenvironments, genetic and epigenetic mutations, phenotypic switching of cells, and the presence of neoantigens. Next, the strategies to overcome drug resistance including blocking alternative pathways that cancer cells use to avoid treatment, using combination therapies that target multiple signaling pathways, and personalizing treatment regimens to account for a patient's genetic and immunologic characteristics have been discussed. Lastly, the need for advanced techniques including transcriptomic, metabolomics, and proteomics in identifying novel targets and therapies to treat hard-to-treat melanoma or skin cancers has been discussed.
黑色素瘤是最常见的皮肤癌类型之一，也是目前最致命的皮肤癌类型。尽管有多种治疗黑色素瘤的药物，但对现有治疗方法的耐药性不断增加是一个主要问题。由于涉及包括基因突变、新抗原的存在、肿瘤微环境和细胞可塑性等复杂机制，肿瘤细胞产生了逃避包括靶向药物和免疫疗法在内的当前治疗效果的能力，从而限制了治疗效果。这导致晚期黑色素瘤患者难以实现长期控制。了解化疗耐药的分子机制对于克服这种耐药性并制定潜在的治疗策略至关重要。在本文中，我们将讨论用于对抗皮肤癌的最常见药物及其抗癌机制，随后讨论内在耐药性和外在耐药性。我们将阐述化疗耐药的分子机制，包括细胞凋亡和脂质代谢的改变、肿瘤微环境的作用、基因和表观遗传突变、细胞表型转换以及新抗原的存在。接下来，我们将讨论克服耐药性的策略，包括阻断癌细胞用于逃避治疗的替代途径、使用针对多种信号通路的联合疗法以及根据患者的基因和免疫特征定制治疗方案。最后，我们讨论了包括转录组学、代谢组学和蛋白质组学在内的先进技术在识别治疗难治性黑色素瘤或皮肤癌的新靶点和新疗法方面的必要性。
