Figure 6

mutRAS melanoma cells are more resistant to DHFR targeting drugs. A, Schematic of nucleotide de novo synthesis and salvage pathways. The asterisks indicate increased activity (IMPDH) or expression (TK1) in mutNRAS cells. B, Average survival of 4 mutBRAF or mutNRAS cell lines after treatment with 4 μM Mycophenolic Acid (MPA) or 5 μM AVN499. **p = 0.01, ***p < 0.001. C, Melanoma cell lines with activating mutations in either BRAF or NRAS were treated with serial increasing concentrations of aminopterin, pyrimethamine or methotrexate. After 3 days, cells were fixed, stained and the GI50 for each drug was calculated. Student’s t test (one-tailed) compares the average GI50 for mutBRAF cell lines vs mutNRAS cell lines. Aminopterin: **p = 0.0092; Pyrimethamine: **p = 0.0071; Methotrexate: ***p = 0.0002. D, Comparison of the IC50 for dypirimethamine of 11 mutBRAF and 7 mutRAS melanoma cell lines, as determined by MTS assay in [25]. *p = 0.0393. E, Graph comparing the IC50 for dypirimethamine between 22 mutBRAF and 22 mutNRAS cell lines from different tumor types [25]. Student’s t test, two-tailed: *p = 0.0184.