@article{819ce932930148d6967282ced32d690b,
title = "Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma",
abstract = "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.",
keywords = "Wnt5A, aged microenvironment, melanoma, slow-cycling phenotype, therapy resistance, tumor microenvironment, wild-type 53",
author = "Webster, {Marie R.} and Fane, {Mitchell E.} and Alicea, {Gretchen M.} and Subhasree Basu and Kossenkov, {Andrew V.} and Marino, {Gloria E.} and Douglass, {Stephen M.} and Amanpreet Kaur and Ecker, {Brett L.} and Keerthana Gnanapradeepan and Abibatou Ndoye and Curtis Kugel and Alexander Valiga and Jessica Palmer and Qin Liu and Xiaowei Xu and Jessicamarie Morris and Xiangfan Yin and Hong Wu and Wei Xu and Cathy Zheng and Karakousis, {Giorgos C.} and Amaravadi, {Ravi K.} and Mitchell, {Tara C.} and Almeida, {Filipe V.} and Min Xiao and Rebecca, {Vito W.} and Wang, {Ying Jie} and Schuchter, {Lynn M.} and Meenhard Herlyn and Murphy, {Maureen E.} and Weeraratna, {Ashani T.}",
note = "Funding Information: We thank the outstanding Core Facilities of the Wistar Institute, supported by P30CA010815. We thank F. Chen, F. Keeney, and J. Faust. A.T.W., A.K., F.A., and G.A. are supported by R01CA174746, and A.T.W., M.F., and S.M.D are supported by R01CA207935. A.N., Q.L., W.X., C.Z., L.S., X.X., G.K., R.K.A., T.M., and A.T.W. are supported by P01 CA114046. A.T.W., R.K.A., L.M.S., and M.H. are also supported by P50 CA174523. M.R.W. is supported by K99 CA208012-01. M.H., L.M.S., G.C.K., T.C.M., and X.X. are supported by the Tara Miller Foundation . M.E.M is supported by R01 CA102184 . M.E.M. and A.T.W. are supported by P01 CA114046 . A.T.W. is also supported by a Melanoma Research Alliance/L{\textquoteright}Or{\'e}al Paris-USA Women in Science Team Science Award , an Established Investigator Award from the Melanoma Research Foundation , P30 CA00697356 , R01CA207935, a Bloomberg Distinguished Professorship, and the E.V. McCollum Chair . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = feb,
day = "6",
doi = "10.1016/j.molcel.2019.11.009",
language = "English (US)",
volume = "77",
pages = "633--644.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",
}