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

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 EC80 divided by the IC80 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.

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B‐rapidly accelerated fibrosarcoma‐mutated advanced melanoma

“…Their development is thought to be induced by a paradoxical activation of the MAPK pathway in BRAF wild-type cells. 35,36 In an in vitro analysis with immortalized human keratinocytes, Adelmann et al 17 have calculated a paradox index to determine the therapeutic window between clinical efficacy and the grade of paradoxical ERK activation of vemurafenib, dabrafenib, encorafenib and PLX8394. The higher the index, the higher the therapeutic window of the tested BRAFi.…”

“…[13][14][15][16] The incidence of cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthomas is particularly high with vemurafenib monotherapy. 17 The frequency and pathogenesis of cuAEs have been thoroughly investigated for the first-generation BRAFi and MEKi. 8,14,15,[18][19][20][21][22][23][24] In contrast, except for reports as part of clinical trial publications, the cuAE profile of encorafenib and/or binimetinib has not been characterized in detail yet.…”

Natural and Biomimetic Antitumor Pyrazoles, A Perspective

“…Molecules 2019, 25, 1364 3 of 12 3: Encorafenib, for the oral treatment of skin cancer [21][22][23][24], and crizotinib [25][26][27], also taken orally and used in lung cancer. This review is organized into two sections.…”

“…It features anti-inflammatory properties in carrageenan-induced mice paw oedema [18], nephroprotecting action in cisplatin-induced mice kidney damage [19], and a caspase-mediated apoptotic effect on lung cancer cells (A549 line) [20]. The pyrazole core is also found in the structure of a few synthetic commercial drugs, such as the nonsteroidal anti-inflammatory agents celecoxib and lonazolac, and two antitumor drugs, represented in Figure 3: Encorafenib, for the oral treatment of skin cancer [21][22][23][24], and crizotinib [25][26][27], also taken orally and used in lung cancer. 3: Encorafenib, for the oral treatment of skin cancer [21][22][23][24], and crizotinib [25][26][27], also taken orally and used in lung cancer.…”

Why do we need a new BRAF-MEK inhibitor combination in melanoma?

“…It differs from other drugs in this group by a more than 10 times longer dissociation half-life (> 30 h), which results in extended inhibition of mitogen-activated protein kinase (MAPK) signalling pathway [10]. It probably results in more potent anti-cancer activity, with a smaller paradoxical upregulation of MAPK pathway in healthy tissues responsible for the development of side effects [10,11]. In turn, binimetinib is a selective inhibitor of MEK1 and MEK2 kinases, which are components of MAPK signalling pathway.…”