Suppression of B-Raf(V600E) cancers by MAPK hyper-activation
| Autor: | Rawan Atiq, Elia Smeir, Sophia Eldad, Rachel Hertz, Jacob Bar-Tana |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine MAPK/ERK pathway medicine.medical_specialty MAP Kinase Signaling System colorectal cancer Palmitic Acids Transfection 03 medical and health sciences ErbB Cell Line Tumor Internal medicine melanoma medicine Humans Thyroid Neoplasms Vemurafenib Protein kinase B Cell Proliferation Insulin-like growth factor 1 receptor B-Raf(V600E) business.industry Kinase Carcinoma Protein phosphatase 2 MAPK Carcinoma Papillary 030104 developmental biology Endocrinology Oncology Thyroid Cancer Papillary papillary thyroid carcinoma Cancer research Mitogen-Activated Protein Kinases Colorectal Neoplasms business HT29 Cells V600E Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.7909 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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