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.
|Romano, Gabriele; Chen, Pei-Ling; Song, Ping et al. (2018) A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. Cancer Discov 8:556-567|
|Hartsough, Edward J; Kugel 3rd, Curtis H; Vido, Michael J et al. (2018) Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo. Mol Cancer Ther 17:84-95|
|Teh, Jessica L F; Aplin, Andrew E (2018) Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment. Clin Cancer Res :|
|Vido, Michael J; Le, Kaitlyn; Hartsough, Edward J et al. (2018) BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association. Cell Rep 25:1501-1510.e3|
|Teh, Jessica L F; Aplin, Andrew E (2018) Playing the Melanoma Endgame. Clin Cancer Res 24:4629-4630|
|Chua, Vivian; Lapadula, Dominic; Randolph, Clinita et al. (2017) Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma. Mol Cancer Res 15:501-506|
|Kageyama, Ken; Ohara, Masahiro; Saito, Kengo et al. (2017) Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis. J Transl Med 15:145|
|Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190|
|Cheng, Hanyin; Chua, Vivian; Liao, Connie et al. (2017) Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma. Mol Cancer Ther 16:516-528|
|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|
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