Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma

• DOI: 10.1016/j.molcel.2020.01.005
• Publication Date: 2020-02-06T15:37:32Z
• Authors: Marie R. Webster; Mitchell E. Fane; Gretchen M. Alicea; Subhasree Basu; Andrew V. Kossenkov; Gloria E. Marino; Stephen M. Douglass; Amanpreet Kaur; Brett L. Ecker; Keerthana Gnanapr...; Abibatou Ndoye; Curtis Kugel; Alexander Valiga; Jessica Palmer; Qin Liu; Xiaowei Xu; Jessicamarie Morris; Xiangfan Yin; Hong Wu; Wei Xu; Cathy Zheng; Giorgos C. Karako...; Ravi K. Amaravadi; Tara C. Mitchell; Filipe V. Almeida; Min Xiao; Vito W. Rebecca; Ying-Jie Wang; Lynn M. Schuchter; Meenhard Herlyn; Maureen E. Murphy; Ashani T. Weeraratna
• Keywords: Proto-Oncogene Proteins B-raf; Sulfonamides; MAP Kinase Kinase Kinases; Wnt-5a Protein; 3. Good health; Drug Resistance, Neoplasm; Cell Line, Tumor; Mutation; Tumor Microenvironment; Humans; Molecular Targeted Therapy; Tumor Suppressor Protein p53; Melanoma; Protein Kinase Inhibitors; Signal Transduction

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.