Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Jana Jandova, Sophia L. Park, Mandi J. Corenblum, Lalitha Madhavan, Jeremy A. Snell, Liliana Rounds, Georg T. Wondrak

Research output: Contribution to journalArticlepeer-review

Abstract

Molecularly targeted therapeutics have revolutionized the treatment of BRAFV600E-driven malignant melanoma, but the rapid development of resistance to BRAF kinase inhibitors (BRAFi) presents a significant obstacle. The use of clinical antimalarials for the investigational treatment of malignant melanoma has shown only moderate promise, attributed mostly to inhibition of lysosomal-autophagic adaptations of cancer cells, but identification of specific antimalarials displaying single-agent antimelanoma activity has remained elusive. Here, we have screened a focused library of clinically used artemisinin-combination therapeutic (ACT) antimalarials for the apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi-resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 vs. BRAFi-resistant A375-BRAFV600E/NRASQ61K). Among ACT antimalarials tested, mefloquine (MQ) was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression-array analysis (A375-BRAFV600E/NRASQ61 vs. A375-BRAFV600E/NRASQ61K) revealed that MQ is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede MQ-induced loss of viability. ER-trackerTM DPX fluorescence imaging and electron microscopy indicated ER swelling, accompanied by rapid induction of ER stress signaling (phospho-eIF2α, XBP-1s, ATF4). Fluo-4 AM-fluorescence indicated the occurrence of cytosolic calcium overload observable within seconds of MQ exposure. In a bioluminescent murine model employing intracranial injection of A375-Luc2 (BRAFV600E/NRASQ61K) 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-resistant.

Original languageEnglish (US)
Pages (from-to)603-614
Number of pages12
JournalMolecular Carcinogenesis
Volume61
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • ER stress
  • NRAS-driven BRAFi-resistance
  • antimalarial chemotherapeutics
  • brain metastases
  • gene expression array analysis
  • malignant melanoma
  • mefloquine

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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