2010 has been called the "Year of Melanoma" by cancer scientists and physicians. In 2011, we witnessed the FDA approval of a BRAF inhibitor (vemurafenib/Zelboraf) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses achieved early are partial (i.e., acute, adaptive resistance), and most patients who initially respond later suffe from disease progression (i.e., acquired drug resistance). In fact, partially regressed melanomas induced by BRAF inhibitors frequently give way to tumor regrowth later due to acquired drug resistance. Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding both early (adaptive, non-genetic) and late (genetic) mechanisms of drug resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. Based on data now under peer review, we hypothesize that early and late drug resistance are mechanistically linked and that epigenetic reprogramming plays a dominant role in early, adaptive drug resistance. The Lo Laboratory has a proven track record in integrating "omic" and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients. These studies have already inspired combinatorial treatment strategies (e.g. BRAF + MEK inhibitors) with encouraging early results. We propose in Aim 1 to leverage whole-exome sequencing to comprehensively understand the mechanisms of acquired (late) BRAF inhibitor resistance in melanoma in order to inform the study of adaptive (early) drug resistance. Here, understanding how a genetic alteration confers acquired drug resistance in a specific cell context will trigger mechanistic studies into this cell context and the implicatd candidate pathway in acute, adaptive resistance.
In Aim 2, we propose experiments to study specific, inter-related epigenetic pathways that contribute to a form of chromatin-mediated acute, adaptive drug resistance.
This aim leverages transcriptomic sequencing and studies early, adaptive resistance as a series of tractable phenotypic states. Overall, our highly translational approaches are founded in innovative collaborations that have already proven productive in yielding novel clinical concepts. Translating knowledge of how melanomas resist BRAF inhibitors back to the clinic promises to make the 2010 melanoma turning point a story for the ages.

Public Health Relevance

Cutaneous melanoma ranks among the fastest rising human malignancies in annual incidence and is highly lethal when detected at advanced stages. Small molecule therapy targeting a common melanoma mutation, V600EBRAF, is showing unprecedented promise but meets a formidable challenge common to all targeted therapy, cancer resistance and clinical relapse. By understanding key mechanisms of epigenetically and genetically driven drug resistance, we can design better diagnostics and therapies to treat this deadly skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176111-01A1
Application #
8595186
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2013-08-07
Project End
2018-06-30
Budget Start
2013-08-07
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$319,550
Indirect Cost
$112,050
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shi, Hubing; Hugo, Willy; Kong, Xiangju et al. (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80-93
Marusiak, Anna A; Edwards, Zoe C; Hugo, Willy et al. (2014) Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors. Nat Commun 5:3901
Shi, Hubing; Hong, Aayoung; Kong, Xiangju et al. (2014) A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov 4:69-79