Abstract 4398: MEK inhibitors prevent rebound reactivation of ERK signaling by the RAF inhibitor PLX4032 and enhance its antitumor activity

Abstract Activation of ERK signaling occurs in the majority of melanomas and tumors with BRAF mutation are especially sensitive to its inhibition with MEK or RAF inhibitors. The latter inhibit ERK signaling only in tumors with V600E mutant BRAF and activate the pathway in cells with WT BRAF. These data implied that RAF inhibitors would have a wider therapeutic index than MEK inhibitors with a greater therapeutic effect, but could also cause toxicity by activating the ERK pathway in normal tissue. These predictions were born out in clinical trials, in which the RAF inhibitor PLX4032 caused tumor regression in most patients with metastatic melanoma with mutant BRAF, but also caused squamous cell carcinoma of the skin in one third of patients. Unfortunately, these responses are rarely complete and the median time to relapse is approximately nine months. We now find that prolonged treatment of BRAF mutant cells with PLX4032 is associated with a rebound of ERK phosphorylation from its nadir that is associated with an increase in the transcriptional output of the pathway and could therefore limit the therapeutic effects of the drug. In this new steady state, ERK phosphorylation and output are sensitive to MEK inhibitors but not readdition of RAF inhibitors. The rebound of ERK signaling is associated with upstream activation in the RAS pathway. We therefore determined the effects of combined RAF and MEK kinase inhibition in a panel of melanoma cells with mutant BRAF. Combined inhibition delayed pathway rebound and resulted in more prolonged suppression of ERK output, enhanced cell death, and tumor growth inhibition compared to treatment with the RAF inhibitor alone. These results suggest that combined RAF and MEK kinase inhibition may be a useful strategy to improve the extent and duration of responses to RAF inhibitors and minimize toxicity caused by ERK activation in normal tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2011-4398

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