Abstract A229: BRAF inhibitors upregulate EGFR ligands: A molecular link to RAF inhibitor-induced cutaneous squamous cell carcinomas

• Published in: Molecular cancer therapeutics Vol. 10; no. 11_Supplement; p. A229
• Main Authors: Ma, Yan, Zhang, Chao, Habets, Gaston, Burton, Elizabeth A., Wong, Bernice, Nguyen, Hoa, Spevak, Wayne, zhang, Jiazhong, Cho, Hanna, Wu, Guoxian, Lin, Jack L., Ewing, Todd, Zhang, Ying, Shi, Songyuan, Nespi, Marika, Tsang, Garson, Marimuthu, Adhirai, Light, Emily, Powell, Ben, Shellooe, Rafe, Tsai, James, West, Brian L., Ibrahim, Prabha N., Hirth, Peter, Bollag, Gideon
• Format: Journal Article
• Language: English
• Published: 12.11.2011
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-A229

Abstract Selective inhibitors of BRAF such as vemurafenib (PLX4032) and GSK2118436 show remarkable efficacy in melanoma patients with tumors harboring BRAF V600 mutations. However these compounds paradoxically activate the MAPK pathway in RAS-mutant cells and are associated clinically with appearance of skin tumors such as cutaneous squamous cell carcinomas (cuSCC), particularly of the keratoacanthoma subtype. Here we further investigated the molecular links between BRAF inhibitor treatment and skin neoplasm. In soft agar, BRAF inhibitors induced growth of HRAS-mutant cuSCC B9 cells via upregulation of several EGFR ligands. The EGFR inhibitor Tarceva antagonized this transforming effect. The “Paradox Breakers,” a class of BRAF inhibitors recently discovered at Plexxikon, did not activate the MAPK pathway in cells with RAS mutation or EGFR family kinase activation and failed to upregulate EGFR ligands or induce soft agar growth of B9 cells. Also when tested in vivo, subcutaneous B9-tumor growth was accelerated by a structural analog (PLX4720) of vemurafenib but not by an equally effective BRAF inhibitor of the Paradox Breaker class. Taken together, a novel mechanism responsible for BRAF inhibitor-induced cuSCC was uncovered. Our data suggest that combination treatment of EGFR inhibitors with BRAF inhibitors might prevent skin tumor growth and that Paradox Breakers represent a new generation of BRAF inhibitors that have fewer unwanted side effects and the potential for greater clinical efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A229.