Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts

Abstract Approximately 50% of metastatic melanoma harbor oncogenic mutations of BRAF, resulting in constitutive activation of the MAPK signaling pathway. Treatment using BRAF and MEK inhibitor combination significantly improved survival in patients with BRAF V600-mutant melanoma. However, the duration of response remains limited as most patients develop resistance. Previously, our group established a collection of patient derived xenografts (PDXs), and conducted a PDX clinical trial using a 1x1x1 experimental design. The PDX clinical trial showed that BRAF V600-mutant melanoma models varied in their response to BRAF and MEK inhibitors, similar to observations in the clinical setting. Therefore, we sought to elucidate the mechanisms governing differential responses to MAPK inhibition in vivo. The PDX models were classified into complete and partial responders based on their sensitivity to BRAF and MEK inhibitors. Using this classification, we characterized the downstream signaling associated with therapeutic response. Whereas complete responders showed almost full suppression of MAPK signaling, partial responders showed heterogeneous levels of MAPK signaling upon BRAF and MEK inhibition. Ongoing work seeks to identify determinants of therapeutic response using biased and unbiased approaches, in an effort to inform combination strategies that improve survival in patients with BRAF V600-mutant melanoma. Citation Format: Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David Ruddy, Darrin Stuart, Matthew Meyer. Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2155.