Suppression of B-Raf(V600E) cancers by MAPK hyper-activation

Rawan Atiq; Rachel Hertz; Sophia Eldad; Elia Smeir; Jacob Bar-Tana

doi:10.18632/oncotarget.7909

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Research Papers:

Suppression of B-Raf(V600E) cancers by MAPK hyper-activation

Rawan Atiq, Rachel Hertz, Sophia Eldad, Elia Smeir and Jacob Bar-Tana _

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Oncotarget. 2016; 7:18694-18704. https://doi.org/10.18632/oncotarget.7909

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Abstract

Rawan Atiq1,*, Rachel Hertz1,*, Sophia Eldad1, Elia Smeir1, Jacob Bar-Tana1

1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120

*These authors contributed equally to this work

Correspondence to:

Jacob Bar-Tana, e-mail: [email protected]

Keywords: B-Raf(V600E), MAPK, melanoma, colorectal cancer, papillary thyroid carcinoma

Received: November 22, 2015 Accepted: February 13, 2016 Published: March 04, 2016

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.

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Research Papers:

Suppression of B-Raf(V600E) cancers by MAPK hyper-activation

Abstract