Project 1: Over the past years, considerable excitement has accompanied the clinical testing of new drugs in melanoma. In particular, the RAF-inhibitor, PLX4032, has showed remarkable efficacy when administered to melanoma patients harboring the BRAFV600E mutation. Unfortunately, the overall clinical benefit of targeted agents in melanoma remains limited, mainly due to the appearance of resistance after a few months of treatment. Work in our lab has discovered different resistance mechanisms involving the appearance of MEK mutant alleles upon treatment of BRAFV600E cells with the MEK inhibitor CI-1040, and the overexpression of CRAF or of MAPK38/COT kinase upon treatment of BRAFV600E cells with the BRAF inhibitor PLX-4720. How general, however, these recently-discovered resistance mechanisms are, remains poorly defined, and, undoubtedly, additional mechanisms of resistance to RAF inhibition remain to be discovered. The purpose of our proposal is to perform a systematic search for novel resistance mechanisms present in, and vulnerabilities of, tumor-derived MAPK-inhibition resistant tumors. This will be addressed by 1) interrogating genetic, as well as "non-genetic" alterations present in patient-derived MAPK-inhibition resistant tumors, by whole-exome and transcriptome sequencing, and 2) identifying novel dependencies unique to MAPK-inhibition resistant tumors, by pooled RNAi screening, and synthetic lethal RNAi screening in the presence of MAPK-inhibitors. In addition, we will establish pre-clinical in vivo mouse models to characterize the recently discovered resistance mechanisms. Upon completion of this research, we will have gained understanding of the resistance mechanisms operant in melanoma, and identified possible new drug targets for combinatorial treatments that could overpower the resistance.

Public Health Relevance

Our study addresses directly this need by performing a comprehensive genomic characterization of patient derived tumors following relapse after RAF/MEK-inhibition-based treatment to identify existing resistant mechanisms, and by performing a molecular characterization of known resistance mechanisms to RAF/MEK inhibition to be able to design of therapeutic regimens to intercept them.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-O (O1))
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Massachusetts General Hospital
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Roider, Elisabeth M; Fisher, David E (2014) The impact of MITF on melanoma development: news from bench and bedside. J Invest Dermatol 134:16-7
Konieczkowski, David J; Johannessen, Cory M; Abudayyeh, Omar et al. (2014) A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov 4:816-27
Van Allen, Eliezer M; Wagle, Nikhil; Sucker, Antje et al. (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4:94-109
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Sullivan, Ryan J; Fisher, David E (2014) Understanding the biology of melanoma and therapeutic implications. Hematol Oncol Clin North Am 28:437-53
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Chen, Hongxiang; Weng, Qing Y; Fisher, David E (2014) UV signaling pathways within the skin. J Invest Dermatol 134:2080-5
Fell, Gillian L; Robinson, Kathleen C; Mao, Jianren et al. (2014) Skin ?-endorphin mediates addiction to UV light. Cell 157:1527-34
Hsiao, Jennifer J; Fisher, David E (2014) The roles of microphthalmia-associated transcription factor and pigmentation in melanoma. Arch Biochem Biophys 563:28-34

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