@article{5ca8919ec1604167b382bce913590fb1,
title = "Targeting PHGDH Upregulation Reduces Glutathione Levels and Resensitizes Resistant NRAS-Mutant Melanoma to MAPK Kinase Inhibition",
abstract = "Melanomas frequently harbor activating NRAS mutations leading to activation of MAPK kinase (MEK) and extracellular signal–regulated kinase 1/2 signaling; however, the clinical efficacy of inhibitors to this pathway is limited by resistance. Tumors rewire metabolic pathways in response to stress signals such as targeted inhibitors and drug resistance, but most therapy-resistant preclinical models are generated in conditions that lack physiological metabolism. We generated human NRAS-mutant melanoma xenografts that were resistant to the MEK inhibitor (MEKi) PD0325901 in vivo. MEKi-resistant cells showed cross-resistance to the structurally distinct MEKi trametinib and elevated extracellular signal–regulated kinase 1/2 phosphorylation and downstream signaling. Additionally, we observed upregulation of the serine synthesis pathway and PHGDH, a key enzyme in this pathway. Suppressing PHGDH in MEKi-resistant cells together with MEKi treatment decreased oxidative stress tolerance and cell proliferation. Together, our data suggest targeting PHGDH as a potential strategy in overcoming MEKi resistance.",
author = "Nguyen, {Mai Q.} and Teh, {Jessica L.F.} and Purwin, {Timothy J.} and Inna Chervoneva and Davies, {Michael A.} and Nathanson, {Katherine L.} and Cheng, {Phil F.} and Levesque, {Mitchell P.} and Reinhard Dummer and Aplin, {Andrew E.}",
note = "Funding Information: The authors would like to thank members of the Aplin lab for their help in offering suggestions, guidance, and technical expertise. The Sidney Kimmel Cancer Center laboratory animal core facility is supported by National Institutes of Health /NCI (P30 CA056036). The reverse-phase protein array studies were performed at the Functional Proteomics Core Facility at The University of Texas MD Anderson Cancer Center , which is supported by an NCI Cancer Center Support Grant (CA16672). This work was supported by grants from National Institutes of Health R01 CA196278, R01 CA182635, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to A.E. Aplin. Funding Information: The authors would like to thank members of the Aplin lab for their help in offering suggestions, guidance, and technical expertise. The Sidney Kimmel Cancer Center laboratory animal core facility is supported by National Institutes of Health/NCI (P30 CA056036). The reverse-phase protein array studies were performed at the Functional Proteomics Core Facility at The University of Texas MD Anderson Cancer Center, which is supported by an NCI Cancer Center Support Grant (CA16672). This work was supported by grants from National Institutes of Health R01 CA196278, R01 CA182635, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to A.E. Aplin. Conceptualization: MQN, JLFT, AEA; Data Curation: MAD, KA, PFC, MPL, RD; Formal Analysis: MQN, TJP, IC; Funding Acquisition: AEA; Investigation: MQN, JLFT; Project Administration: MQN, AEA; Software: TJP; Supervision: AEA; Validation: MQN; Visualization: MQN; Writing - Original Draft Preparation: MQN; Writing - Review and Editing: MQN, JLFT, MAD, AEA Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = nov,
doi = "10.1016/j.jid.2020.02.047",
language = "English (US)",
volume = "140",
pages = "2242--2252.e7",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "11",
}