Abstract RAF and MEK inhibitors are used to target malignant melanomas harbouring BRAF V600E mutations, but resistance to these therapies remains a significant challenge. Here we conducted a screen of 450 secreted peptides to identify possible cell-autonomous or microenvironment-driven mechanisms of resistance to RAF and MEK inhibitors in ten melanoma cell lines. We identified multiple receptor tyrosine kinase (RTK)-mediated resistance mechanisms and show that drug-resistance in vitro was driven by mechanisms predicted by the screen and that co-targeting FGFR and BRAF prevents tumour regrowth in vivo. We also found that cells can become resistant to rational combinations of targeted inhibitors in a serial manner, again predicted by the screen. In many cases resistance is mediated by reactivation of MAPK-signalling, however, there is also evidence for non-MAPK-dependent mechanisms of resistance once these are exhausted. These data reveal multiple, defined mechanisms of resistance as well as highlight potential challenges of overcoming therapeutic resistance in a highly adaptive tumour type. Citation Format: Nicholas A. Dompe, Eva Lin, Jing Peng, Grace Chan, Grace Chan, Grace Chan, Janet Tien, Mark Merchant, Richard Bourgon, Jeffrey Settleman, Timothy Wilson, Richard M. Neve. Potential combinatorial strategies to overcome drug resistance in BRAF-mutant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B22.