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Abstract 2841: A co-clinical assessment of patterns of BRAF inhibitor resistance

2015; American Association for Cancer Research; Volume: 75; Issue: 15_Supplement Linguagem: Inglês

10.1158/1538-7445.am2015-2841

1538-7445

Lawrence N. Kwong, Genevieve M. Boland, Dennie T. Frederick, Timothy L. Helms, Ahmad T. Akid, John Miller, Shan Jiang, Zachary A. Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon B. Mills, Keith T. Flaherty, Jennifer A. Wargo, Lynda Chin,

Computational Drug Discovery Methods

Abstract Multiple mechanisms conferring resistance of melanomas to BRAF inhibitors have been described, yet the basis of resistance in a sizeable portion of patient samples remains undefined. To address this gap, we characterized patients’ baseline, on-treatment, and resistant tumors on both the protein and RNA levels. By RNA-sequencing, we identified known resistance-conferring mutations in 50% (6/12) of the resistant samples. In parallel, targeted proteomic analysis by protein array categorized the resistant samples into three stable groups: two that reactivate MAPK signaling to different levels, and one that is MAPK-independent. The molecular relevance of these categories was supported by both mutation data and the similarity of resistance patterns that emerged in a co-clinical trial in a novel genetically engineered mouse model. Additionally, we have defined biomarkers in pre- and early-treatment patient samples that have potential for predicting clinical responses. On the basis of these observations, we suggest that BRAF inhibitor-resistant melanomas can be actionably categorized using protein patterns, even without the identification of the underlying genetic alteration. Citation Format: Lawrence N. Kwong, Genevieve Boland, Dennie Frederick, Timothy Helms, Ahmad Akid, John Miller, Shan Jiang, Zachary Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon Mills, Keith Flaherty, Jennifer Wargo, Lynda Chin. A co-clinical assessment of patterns of BRAF inhibitor resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2841. doi:10.1158/1538-7445.AM2015-2841