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.
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.
|Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102|
|Kwong, Lawrence N; Zou, Lihua; Chagani, Sharmeen et al. (2017) Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma. Cell Rep 19:1304-1312|
|Du, Wanlu; Seah, Ivan; Bougazzoul, Oumaima et al. (2017) Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. Proc Natl Acad Sci U S A 114:E6157-E6165|
|Mujahid, Nisma; Liang, Yanke; Murakami, Ryo et al. (2017) A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin. Cell Rep 19:2177-2184|
|Song, J S; London, W B; Hawryluk, E B et al. (2017) Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52:989-997|
|Alves, Cleidson P; Yokoyama, Satoru; Goedert, Lucas et al. (2017) MYO5A Gene Is a Target of MITF in Melanocytes. J Invest Dermatol 137:985-989|
|Friedman, Adam A; Xia, Yun; Trippa, Lorenzo et al. (2017) Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations. Clin Cancer Res 23:4680-4692|
|Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153|
|Osseiran, Sam; Roider, Elisabeth M; Wang, Hequn et al. (2017) Non-Euclidean phasor analysis for quantification of oxidative stress in ex vivo human skin exposed to sun filters using fluorescence lifetime imaging microscopy. J Biomed Opt 22:1-10|
|Xia, Yun; Li, Ying; Westover, Kenneth D et al. (2016) Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and ?-Mangostin. PLoS One 11:e0155217|
Showing the most recent 10 out of 62 publications