Molecular cell · 2019
Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Webster Marie R, Fane Mitchell E, Alicea Gretchen M, Basu Subhasree, Kossenkov Andrew V, Marino Gloria E, Douglass Stephen M, Kaur Amanpreet, Ecker Brett L, Gnanapradeepan Keerthana, Ndoye Abibatou, Kugel Curtis, Valiga Alexander, Palmer Jessica, Liu Qin, Xu Xiaowei, Morris Jessicamarie, Yin Xiangfan, Wu Hong, Xu Wei, Zheng Cathy, Karakousis Giorgos C, Amaravadi Ravi K, Mitchell Tara C, Almeida Filipe V, Xiao Min, Rebecca Vito W, Wang Ying-Jie, Schuchter Lynn M, Herlyn Meenhard, Murphy Maureen E, Weeraratna Ashani T
Аннотация
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.