Targeting N-RAS as a Therapeutic Approach for Melanoma
Abstract
Activating mutations in N-RAS are found in 33% of primary melanomas, and are correlated with sun exposure and nodular lesions. Potential therapeutic strategies have been devised in the past to "directly" target RAS. Unfortunately, these have shown minimal if any activity in melanoma in clinical trials, because wild-type Ras and its downstream effectors are required for many critical cellular functions in normal cells, the therapeutic window for inhibiting Ras directly may be too narrow to exploit. Our novel alternative strategy has the potential to circumvent this limitation. Aberrantly activated, K-RAS or Ha-RAS are lethal to a tumor cell unless a survival pathway requiring PKCd is also active. Inhibition of PKCd in human and murine cells containing an activated K- or Ha-RAS protein initiates rapid and profound apoptosis. The dependency of tumor cells upon the activity of a non-oncogenic protein is sometimes termed "non-oncogene addiction." Hypothesis: inhibition or down-regulation of PKCd in human and murine models of melanoma with aberrant activation of N-RAS signaling will cause targeted cytotoxicity in these tumors. The Specific Aims/Study Design of this Discovery Proposal are: Test the hypothesis that inhibition or downregulation of PKCd in human melanoma cell lines with NRAS mutations selectively induces apoptosis; 2) Determine whether aberrant activation of pathways downstream of RAS (in the setting of wild-type RAS alleles) will similarly sensitize human melanoma cells to PKCd inhibition; 3) Test this targeted approach in in vivo models of human melanoma. Impact: A novel therapeutic modality selectively targeting melanomas with activation of N-RAS would make a significant impact on the way melanoma is treated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2014
- Accession Number
- ADA622292
Entities
People
- Douglas V. Faller