Comparative profiles of BRAF inhibitors: The paradox index as a predictor of clinical toxicity

// Charles H. Adelmann 1 , Grace Ching 1 , Lili Du 1 , Rachael C. Saporito 1 , Varun Bansal 1 , Lindy J. Pence 1 , Roger Liang 1 , Woojin Lee 1 , Kenneth Y. Tsai 1, 2, 3 1 Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA 2 Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA 3 Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA Correspondence to: Kenneth Y. Tsai, email: kytsai@mdanderson.org Keywords: BRAF, squamous cell carcinoma, small molecule inhibitor, paradoxical ERK, melanoma Received: November 26, 2015     Accepted: March 04, 2016     Published: March 25, 2016 ABSTRACT BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by “paradoxical ERK activation,” or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher “paradox indices”, defined as the pERK activation EC 80 divided by the IC 80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.