School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Western Australia, Australia.
School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Western Australia, Australia.
Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129736. doi: 10.1016/j.bbagen.2020.129736. Epub 2020 Sep 18.
The introduction of targeted therapies for the treatment of BRAF-mutant melanomas have improved survival rates in a significant proportion of patients. Nonetheless, the emergence of resistance to treatment remains inevitable in most patients.
Here, we review known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition in melanoma cells and the potential strategies to overcome these mechanisms.
Multiple genetic and non-genetic mechanisms contribute to treatment failure, commonly leading to the reactivation of the MAPK pathway. A variety of resistance mechanisms are enabled by the underlying heterogeneity and plasticity of melanoma cells. Moreover, it has become apparent that resistance to targeted therapy is underpinned by early functional adaptations involving the rewiring of cell states and metabolic pathways.
The evidence presented suggest that the use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes.
针对 BRAF 突变型黑色素瘤的靶向治疗方法的引入，显著提高了相当一部分患者的生存率。然而，大多数患者不可避免地会出现治疗耐药。
本文综述了已知和新兴的分子机制，这些机制是黑色素瘤细胞对 MAPK 抑制产生耐药性的基础，以及克服这些机制的潜在策略。
多种遗传和非遗传机制导致治疗失败，通常导致 MAPK 通路的重新激活。黑色素瘤细胞的异质性和可塑性使多种耐药机制成为可能。此外，靶向治疗耐药的基础是早期涉及细胞状态和代谢途径重布线的功能适应。
提出的证据表明，联合治疗方法的应用将延迟耐药的出现并改善患者的预后。
