Skin Cancer Centre Charité, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Clinical Medicine, University of South China, Hengyang 421001, China.
Int J Mol Sci. 2023 Mar 4;24(5):4961. doi: 10.3390/ijms24054961.
Targeting of MAP kinase pathways by BRAF inhibitors has evolved as a key therapy for BRAF-mutated melanoma. However, it cannot be applied for BRAF-WT melanoma, and also, in BRAF-mutated melanoma, tumor relapse often follows after an initial phase of tumor regression. Inhibition of MAP kinase pathways downstream at ERK1/2, or inhibitors of antiapoptotic Bcl-2 proteins, such as Mcl-1, may serve as alternative strategies. As shown here, the BRAF inhibitor vemurafenib and the ERK inhibitor SCH772984 showed only limited efficacy in melanoma cell lines, when applied alone. However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. This resulted in up to 90% loss of cell viability and cell proliferation, as well as in induction of apoptosis in up to 60% of cells. The combination of SCH772984/S63845 resulted in caspase activation, processing of poly (ADP-ribose) polymerase (PARP), phosphorylation of histone H2AX, loss of mitochondrial membrane potential, and cytochrome c release. Proving the critical role of caspases, a pan-caspase inhibitor suppressed apoptosis induction, as well as loss of cell viability. As concerning Bcl-2 family proteins, SCH772984 enhanced expression of the proapoptotic Bim and Puma, as well as decreased phosphorylation of Bad. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.
靶向 MAP 激酶途径的 BRAF 抑制剂已成为 BRAF 突变黑色素瘤的关键治疗方法。然而，它不能应用于 BRAF-WT 黑色素瘤，并且在 BRAF 突变的黑色素瘤中，肿瘤复发通常在肿瘤消退的初始阶段之后发生。抑制 ERK1/2 下游的 MAP 激酶途径，或抑制抗凋亡 Bcl-2 蛋白，如 Mcl-1，可能是替代策略。如这里所示，BRAF 抑制剂 vemurafenib 和 ERK 抑制剂 SCH772984 单独应用时，在黑色素瘤细胞系中仅显示出有限的疗效。然而，与 Mcl-1 抑制剂 S63845 联合应用时，vemurafenib 在 BRAF 突变细胞系中的作用得到了显著增强，SCH772984 在 BRAF 突变和 BRAF-WT 细胞中的作用也得到了增强。这导致细胞活力和细胞增殖高达 90%的损失，以及高达 60%的细胞凋亡诱导。SCH772984/S63845 的组合导致半胱天冬酶激活、多聚（ADP-核糖）聚合酶（PARP）的加工、组蛋白 H2AX 的磷酸化、线粒体膜电位的丧失和细胞色素 c 的释放。证明半胱天冬酶的关键作用，一种泛半胱天冬酶抑制剂抑制了凋亡诱导以及细胞活力的丧失。关于 Bcl-2 家族蛋白，SCH772984 增强了促凋亡 Bim 和 Puma 的表达，并降低了 Bad 的磷酸化。最终，组合导致抗凋亡 Bcl-2 的下调和促凋亡 Noxa 的表达增强。总之，ERK 和 Mcl-1 的联合抑制在 BRAF 突变和 WT 黑色素瘤细胞中均显示出令人印象深刻的疗效，因此可能代表克服耐药性的一种新策略。
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