Abstract
BackgroundThe importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents.MethodsUsing cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors.ResultsAlthough both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors.ConclusionIn summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs.
Highlights
The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent
NRAS mutant melanoma cells are less responsive to DTIC than BRAF mutant cells To address the potential influence of the genetic background on the response of melanoma cells to chemotherapeutic agents, we tested three different classes of DNA damaging agents: carmustine, cisplatin and DTIC in 9 NRAS mutant and 9 BRAF mutant melanoma cell lines
To establish that this gives rise to a DNA alkylating agent, we quantified O6meG levels in DNA extracted from DTIC-treated cells and compared them with the levels in TMZ-treated cells
Summary
The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. While there is no efficient targeted therapy against wild type BRAF melanomas, BRAF mutant (mutBRAF) melanomas are addicted to the MAPK-pathway and small molecule inhibitors targeting either mutBRAF or MEK have shown impressive clinical responses [4,5,6,7]. These responses are transient, and patient relapse due to acquired resistance [8]. Despite the initial successes with BRAF targeted therapy, relapsed patients as well as the 50% of patients harbouring a wild type BRAF (including the 25% with NRAS mutations) will still require alternative treatment such as chemotherapy and/or immunotherapy
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