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The use of clinical antimalarials for the investigational treatment of malignant melanoma has shown only moderate promise, attributed mostly to inhibition of lysosomal\u2010autophagic adaptations of cancer cells, but identification of specific antimalarials displaying single\u2010agent antimelanoma activity has remained elusive. Here, we have screened a focused library of clinically used artemisinin\u2010combination therapeutic (ACT) antimalarials for the apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi\u2010resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi\u2010sensitive A375\u2010BRAF<jats:sup>V600E<\/jats:sup>\/NRAS<jats:sup>Q61<\/jats:sup> vs. BRAFi\u2010resistant A375\u2010BRAF<jats:sup>V600E<\/jats:sup>\/NRAS<jats:sup>Q61K<\/jats:sup>). Among ACT antimalarials tested, mefloquine (MQ) was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression\u2010array analysis (A375\u2010BRAF<jats:sup>V600E<\/jats:sup>\/NRAS<jats:sup>Q61<\/jats:sup> vs. A375\u2010BRAF<jats:sup>V600E<\/jats:sup>\/NRAS<jats:sup>Q61K<\/jats:sup>) revealed that MQ is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede MQ\u2010induced loss of viability. ER\u2010tracker<jats:sup>TM<\/jats:sup> DPX fluorescence imaging and electron microscopy indicated ER swelling, accompanied by rapid induction of ER stress signaling (phospho\u2010eIF2\u03b1, XBP\u20101s, ATF4). Fluo\u20104 AM\u2010fluorescence indicated the occurrence of cytosolic calcium overload observable within seconds of MQ exposure. In a bioluminescent murine model employing intracranial injection of A375\u2010Luc2 (BRAF<jats:sup>V600E<\/jats:sup>\/NRAS<jats:sup>Q61K<\/jats:sup>) cells, an oral MQ regimen efficiently antagonized brain tumor growth. Taken together, these data suggest that the clinical antimalarial MQ may be a valid candidate for drug repurposing aiming at chemotherapeutic elimination of malignant melanoma cells, even if metastasized to the brain and BRAFi\u2010resistant.<\/jats:p>","DOI":"10.1002\/mc.23407","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T12:41:56Z","timestamp":1649853716000},"page":"603-614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mefloquine induces ER stress and apoptosis in BRAFi\u2010resistant A375\u2010BRAF<sup>V600E<\/sup>\/NRAS<sup>Q61K<\/sup> malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model"],"prefix":"10.1002","volume":"61","author":[{"given":"Jana","family":"Jandova","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, RK Coit College of Pharmacy &amp;\u00a0The University of Arizona Cancer Center University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia L.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, RK Coit College of Pharmacy &amp;\u00a0The University of Arizona Cancer Center University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandi J.","family":"Corenblum","sequence":"additional","affiliation":[{"name":"Department of Neurology, Evelyn F McKnight Brain Institute and BIO5 Institute University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalitha","family":"Madhavan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Evelyn F McKnight Brain Institute and BIO5 Institute University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy A.","family":"Snell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, RK Coit College of Pharmacy &amp;\u00a0The University of Arizona Cancer Center University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Rounds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, RK Coit College of Pharmacy &amp;\u00a0The University of Arizona Cancer Center University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg T.","family":"Wondrak","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, RK Coit College of Pharmacy &amp;\u00a0The University of Arizona Cancer Center University of Arizona Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2034861"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00202"},{"issue":"21","key":"e_1_2_10_4_1","first-page":"02368","article-title":"Vemurafenib drives epithelial\u2010to\u2010mesenchymal transition gene expression in BRAF inhibitor\u2010resistant BRAF(V600E)\/NRAS(Q61K) melanoma enhancing tumor growth and metastasis in a bioluminescent murine model","volume":"0022","author":"Jandova J","year":"2021","journal-title":"J Invest 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