The RAF inhibitors, vemurafenib (PLX4032/Zelboraf) and dabrafenib, are the current first-line treatment options for late-stage mutant BRAF melanoma. Objective responses to vemurafenib/dabrafenib in patients are associated with greater than 80% inhibition of ERK1/2 signaling, as measured by immunohistochemical staining. However, the long-term efficacy of current RAF inhibitors is limited by acquired resistance in mutant BRAF cells and paradoxical ERK1/2 activation in wild-type BRAF cells. In this proposal, we outline a novel in vivo reporter system to measure ERK1/2 pathway activity in a non-invasive, quantitative and temporal manner in mutant BRAF melanoma cells. We have utilized this system to provide novel mechanistic insight into acquired resistance to vemurafenib. We also show that a new class of RAF inhibitors that do not elicit paradoxical ERK1/2 activation may provide inhibits growth of vemurafenib-resistant melanoma cells. Here, we will propose to further define mechanisms underlying resistance to vemurafenib, and to determine the effects and modes of resistance to this new class of RAF inhibitors. At the completion of our experiments, we expect to have provided the preclinical basis for new first-line for mutant BRAF melanoma and second-line treatment options for vemurafenib/dabrafenib-resistant melanomas.
Melanoma is the deadliest form of skin cancer. Targeted RAF inhibitors have dramatically changed the first-line treatment options for many melanoma patients but these therapeutics are hampered by side effects and acquired resistance leading to disease progression. This application utilizes a novel in vivo system and analyzes next generation RAF inhibitors aiming to provide the preclinical basis for future treatment options.
|Boregowda, Rajeev K; Medina, Daniel J; Markert, Elke et al. (2016) The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget 7:29689-707|
|Hartsough, Edward J; Aplin, Andrew E (2016) Of Mice and Melanoma: PDX System for Modeling Personalized Medicine. Clin Cancer Res 22:1550-2|
|Teh, Jessica L F; Purwin, Timothy J; Greenawalt, Evan J et al. (2016) An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma. Cancer Res 76:5455-66|
|Vu, Ha Linh; Aplin, Andrew E (2016) Targeting mutant NRAS signaling pathways in melanoma. Pharmacol Res 107:111-6|
|Vido, Michael J; Aplin, Andrew E (2015) The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox. J Invest Dermatol 135:2355-7|
|Shao, Yongping; Le, Kaitlyn; Cheng, Hanyin et al. (2015) NF-ÎºB Regulation of c-FLIP Promotes TNFÎ±-Mediated RAF Inhibitor Resistance in Melanoma. J Invest Dermatol 135:1839-48|