Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland.
Department of Biology/Whitney Laboratory for Marine Bioscience, University of Florida, Gainesville, FL, USA.
Life Sci Alliance. 2022 Aug 29;5(10). doi: 10.26508/lsa.202201445. Print 2022 Oct.
The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAF mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase-independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAFi. We show that the BRAF mutant protein, but not the wild-type BRAF protein, binds to MST2 inhibiting its proapoptotic signalling. Down-regulation of MST2 reduces BRAFi-induced apoptosis. In BRAFi-resistant cell lines, MST2 pathway proteins are down-regulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway-induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAFi resistance in melanoma.
RAS-RAF-MEK-ERK 通路在大多数恶性黑色素瘤中被过度激活，而 BRAF 或 NRAS 的突变占了这些病例的大多数。BRAF 抑制剂（BRAFi）在治疗携带 BRAF 突变的患者方面非常有效，但肿瘤在几个月内经常会产生耐药性。由于复活 ERK 信号的突变或网络适应，已经确定了多种耐药机制。我们之前曾表明，RAF 蛋白以非激酶依赖的方式抑制 MST2 促凋亡途径。在这里，我们研究了 MST2 途径在介导 BRAFi 耐药中的作用。我们表明，BRAF 突变蛋白，但不是野生型 BRAF 蛋白，与 MST2 结合抑制其促凋亡信号。MST2 的下调减少了 BRAFi 诱导的细胞凋亡。在 BRAFi 耐药细胞系中，MST2 途径蛋白通过泛素化和随后的蛋白酶体降解而下调，使细胞对 MST2 途径诱导的细胞凋亡产生抗性。通过使用蛋白酶体抑制剂增加 MST2 途径蛋白的表达，可以实现凋亡的恢复。总之，我们表明 MST2 途径在黑色素瘤获得 BRAFi 耐药性中起作用。
