1. Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.
- Author
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Webster MR, Fane ME, Alicea GM, Basu S, Kossenkov AV, Marino GE, Douglass SM, Kaur A, Ecker BL, Gnanapradeepan K, Ndoye A, Kugel C, Valiga A, Palmer J, Liu Q, Xu X, Morris J, Yin X, Wu H, Xu W, Zheng C, Karakousis GC, Amaravadi RK, Mitchell TC, Almeida FV, Xiao M, Rebecca VW, Wang YJ, Schuchter LM, Herlyn M, Murphy ME, and Weeraratna AT
- Subjects
- Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Humans, MAP Kinase Kinase Kinases metabolism, Melanoma genetics, Melanoma pathology, Molecular Targeted Therapy, Mutation drug effects, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Signal Transduction drug effects, Sulfonamides pharmacology, Tumor Microenvironment drug effects, Tumor Suppressor Protein p53 physiology, Melanoma metabolism, Tumor Suppressor Protein p53 genetics, Wnt-5a Protein metabolism
- 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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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