title: Suppression of B-Raf(V600E) cancers by MAPK hyper-activation.
abstract: B-Raf(V600E) activates MEK/MAPK signalling and acts as oncogenic driver of a variety of cancers, including melanoma, colorectal and papillary thyroid carcinoma. Specific B-Raf(V600E) kinase inhibitors (e.g., Vemurafenib) prove initial efficacy in melanoma followed shortly by acquired resistance, while failing in most other B-Raf(V600E) cancers due to primary resistance. Resistance is due to acquired mutations in the Ras/Raf/MEK/MAPK pathway and/or other oncogenic drivers that bypass B-Raf(V600E). Surprisingly, hyper-activation of MAPK by inhibiting its protein phosphatase 2A by a synthetic long-chain fatty acid analogue (MEDICA), results in oncogene-induced growth arrest and apoptosis of B-Raf(V600E) cancer cells. Growth arrest is accompanied by MAPK-mediated serine/threonine phosphorylation and suppression of a variety of oncogenic drivers that resist treatment by B-Raf(V600E) kinase inhibitors, including ErbB members, c-Met, IGFR, IRS, STAT3 and Akt. The combined activities of mutated B-Raf and MEDICA are required for generating hyper-activated MAPK, growth arrest and apoptosis, implying strict specificity for mutated B-Raf cancer cells.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Rawan
authors.initials: R
authors.lastname: Atiq
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Sophia
authors.initials: S
authors.lastname: Eldad
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Elia
authors.initials: E
authors.lastname: Smeir
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000473:pathology; D014162:Transfection
chemical_list: D010169:Palmitic Acids; C012346:hexadecanedioic acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: B-Raf(V600E); MAPK; colorectal cancer; melanoma; papillary thyroid carcinoma