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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA182635-01A1
Application #
8774480
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19107