PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma

The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK.未折叠蛋白反应（unfolded protein response, UPR）可调控细胞暴露于内质网应激后的细胞命运。PERK作为一种UPR相关蛋白激酶，可调控蛋白质合成；其虽与细胞存活密切相关，但同时兼具与肿瘤进展及肿瘤抑制相关的双重活性。例如，缺失PERK的细胞对UPR介导的细胞死亡更为敏感，而PERK的急性激活可同时触发细胞凋亡与细胞周期阻滞，这一效应被认为有助于发挥肿瘤抑制活性。本研究在BRAF依赖性黑色素瘤中评估了PERK的上述活性，并揭示了PERK在黑色素瘤中发挥的复杂调控作用：PERK表达降低50%即可促进BRAF V600E依赖性细胞转化，而完全抑制PERK则可发挥肿瘤抑制作用。与此一致的是，在人类黑色素瘤中鉴定出的PERK突变体均为功能减退型，且具备显性抑制功能。值得注意的是，本研究证实小分子PERK抑制剂单药即可对BRAF V600E依赖性肿瘤产生疗效，凸显了靶向PERK的临床应用价值。