Fig. 5: ARF6 inhibition sensitizes MAPKi-resistant cells.
From: Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance
a Schematics of in vivo and in vitro experiments with patient-derived xenograft cell lines. b Rate of tumor growth measurements started six days after initial engraftment of MTG013 cells [stably transduced with doxycycline-induced short hairpin RNA (shRNA) for ARF6] in NRG mice, n = 10 controls fed regular chow, n = 10 fed doxycycline chow (shARF6). Tumor growth rate: two-tailed unpaired t-test with Welch’s correction. Tumor growth: Two-way ANOVA, error bars = SD. c, e, g, h, j, k, l Cell viability detection measured at 48 h in patient-derived cell lines (see Supplementary Table 1). c Dose response to Dabrafenib plus Trametinib (Dab+Tram) in MTG013, n = 5 replicates per condition, error bars = SD. d Schematic showing interpretation of following cell viability assays. e, f Doxycycline-induced shARF6. e n = 4 replicates per condition. f Apoptosis detection. n = 3 replicates per condition. g, h, i, k, l Pharmacologic inhibition of ARF6. g, h n = 5 replicates per condition. i, m Colony outgrowth assay in MTG013 and MTG030 for 14 days. Two-tailed unpaired t-test. i MTG013 treated with 5 μM Dabrafenib and 0.25 μM Trametinib ± 1.25 μM NAV-2729. n = 4 biological independent experiments. j Dose response of Dab+Tram in MTG030. n = 5 replicates per condition, error bars = SD. k, l n = 4 replicates per condition. m MTG030 treated with 5 μM Dabrafenib and 0.25 μM Trametinib, Ctrl=no doxycycline. n = 4 biological independent experiments. e, f, g, h, k, l One-way ANOVA with multiple comparisons.
