Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.

中文翻译：

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野生型p53在黑色素瘤驱动治疗耐药性中的悖论作用。

尽管最近在治疗上有所改进，但转移性黑素瘤仍是一种侵袭性疾病。即使在药物敏感的肿瘤中，也无法根除所有黑色素瘤细胞，因为一部分细胞可以转变为慢循环状态，从而使其对大多数靶向治疗都具有抵抗力。尚不清楚什么途径定义这些亚群并促进这种抗性表型。在当前的研究中，我们表明Wnt5A是一种非典型的Wnt配体，可驱动转移性，抗治疗性表型，稳定p53的半衰期，并利用p53在应激后启动慢循环状态（DNA损伤，靶向治疗和衰老）。抑制p53可阻断慢循环表型，并使黑色素瘤细胞对BRAF / MEK抑制敏感。体内，在BRAF / MEK抑制剂治疗开始时，可​​以单剂量使用p53抑制剂来实现这一目标。这些数据表明，采取抑制而不是激活野生型p53的悖论方法可能会使先前耐药的转移性黑色素瘤细胞对治疗敏感。