Roche Pharma Research and Early Development, Oncology Discovery, Roche Innovation Center Basel, Basel, Switzerland.
Roche Pharma Research and Early Development, Informatics, Roche Innovation Center Basel, Basel, Switzerland.
Life Sci Alliance. 2022 May 17;5(9). doi: 10.26508/lsa.202101235. Print 2022 Sep.
MAPK inhibitors (MAPKi) remain an important component of the standard of care for metastatic melanoma. However, acquired resistance to these drugs limits their therapeutic benefit. Tumor cells can become refractory to MAPKi by reactivation of ERK. When this happens, tumors often become sensitive to drug withdrawal. This drug addiction phenotype results from the hyperactivation of the oncogenic pathway, a phenomenon commonly referred to as oncogene overdose. Several feedback mechanisms are involved in regulating ERK signaling. However, the genes that serve as gatekeepers of oncogene overdose in mutant melanoma remain unknown. Here, we demonstrate that depletion of the ERK phosphatase, DUSP4, leads to toxic levels of MAPK activation in both drug-naive and drug-resistant mutant melanoma cells. Importantly, ERK hyperactivation is associated with down-regulation of lineage-defining genes including Our results offer an alternative therapeutic strategy to treat mutant melanoma patients with acquired MAPKi resistance and those unable to tolerate MAPKi.
MAPK 抑制剂（MAPKi）仍然是转移性黑色素瘤标准治疗的重要组成部分。然而，这些药物的获得性耐药限制了它们的治疗效果。肿瘤细胞可以通过 ERK 的重新激活而对 MAPKi 产生抗药性。当这种情况发生时，肿瘤通常对药物停药变得敏感。这种药物成瘾表型是由于致癌途径的过度激活引起的，这种现象通常被称为致癌基因过载。有几个反馈机制参与调节 ERK 信号。然而，在突变黑色素瘤中充当致癌基因过载的“守门员”的基因仍然未知。在这里，我们证明 ERK 磷酸酶 DUSP4 的耗竭会导致在无药和耐药突变黑色素瘤细胞中 MAPK 过度激活到毒性水平。重要的是，ERK 的过度激活与谱系定义基因的下调有关，包括我们的研究结果为治疗获得性 MAPKi 耐药和不能耐受 MAPKi 的突变黑色素瘤患者提供了一种替代治疗策略。
