Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
Sci Transl Med. 2013 Jul 31;5(196):196ra98. doi: 10.1126/scitranslmed.3005753.
RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. However, most responses are partial and short-lived, and many patients fail to respond at all. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein S6 (P-S6), effectively predicted induction of cell death by the inhibitor in BRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was maintained after treatment with RAF or MEK inhibitors, in some cases despite robust suppression of mitogen-activated protein kinase (MAPK) signaling. In in vivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response. Finally, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression predicted significantly improved progression-free survival. Such a change in P-S6 could be readily monitored in real time by serial fine-needle aspiration biopsies, making quantitation of P-S6 a valuable biomarker to guide treatment in BRAF-mutant melanoma.
RAF 和 MEK（丝裂原活化或细胞外信号调节蛋白激酶激酶）抑制剂在治疗 BRAF 突变型黑色素瘤患者方面非常有效。然而，大多数反应是部分的且短暂的，许多患者根本没有反应。我们发现，TORC1 活性的抑制（通过核糖体蛋白 S6 的磷酸化（P-S6）减少来衡量）对 RAF 或 MEK 抑制剂的反应有效地预测了抑制剂在 BRAF 突变型黑色素瘤细胞系中诱导细胞死亡的能力。在耐药性黑色素瘤中，TORC1 活性在 RAF 或 MEK 抑制剂治疗后得以维持，在某些情况下，尽管 MAPK（丝裂原活化蛋白激酶）信号被强烈抑制。在体内小鼠模型中，MAPK 抑制后 TORC1 的抑制对于诱导细胞凋亡和肿瘤反应是必需的。最后，在接受 RAF 抑制剂治疗之前和之后获得的 BRAF 突变型黑色素瘤患者的配对活检中，P-S6 的抑制预示着无进展生存期显著改善。P-S6 的这种变化可以通过连续细针抽吸活检进行实时监测，使得 P-S6 的定量成为指导 BRAF 突变型黑色素瘤治疗的有价值的生物标志物。
