Fig. 4: Dual KRAS–MAPK and PIKfyve inhibition results in metabolic crises and synergistic growth suppression in PDAC.
From: Targeting PIKfyve-driven lipid metabolism in pancreatic cancer
a, Immunoblot analysis of 7940B cells treated with trametinib or MRTX1133 for 48 h. Vinculin served as a loading control. MRTX1133 and DMSO were refreshed every 12 h. b, Quantitative PCR (qPCR) of iKRAS 9805 cells after 48 h incubation with or without doxycycline (Dox) and subsequent 8-hour treatment with apilimod (AP, 50 nM), ESK981 (ESK, 300 nM) or DMSO for the genes Fasn and Acaca. Bars are ±s.d. (multiple unpaired two-tailed t-tests). c, Immunoblot analysis of iKRAS 9805 cells after 48 h incubation with or without doxycycline and subsequent 24 h treatment with apilimod (50 nM), ESK981 (300 nM) or DMSO. Vinculin served as a loading control. d, End-point pancreas + tumour weight normalized to total body weight. Pancreata of six age-matched non-tumour-bearing C57BL/6 mice were used as references. Boxes represent 25th and 75th percentiles; whiskers represent the range (one-way ANOVA with Tukey’s test); NS, not significant. e, Quantification of the proportion of PDAC in H&E sections from each tumour in d. Boxes represent 25th and 75th percentiles; whiskers represent the range (one-way ANOVA with Tukey’s test). f, Representative images of CK19 IHC staining of one tumour from each treatment arm in d. Scale bar, 5 mm. g, Tumour volumes (as a percentage of the initial volume) over the treatment course of the UM19 tumour model treated with trametinib ± ESK981. Bars show s.e.m. (two-way ANOVA with Šidák’s correction). The mice in the vehicle-treated and ESK981-treated groups are the same mice shown in Extended Data Fig. 12k–m. h, Kaplan–Meier estimates of time to tumour doubling for the mice in g (two-sided log-rank tests). i, Kaplan–Meier survival curves of KPC mice undergoing the treatments indicated (two-sided log-rank tests). The mice in the vehicle-treated and ESK981-treated groups are the same mice shown in Extended Data Fig. 12o–s. j, Tumour volumes of the KPC mice in i, measured by ultrasound.
