Figure 4 |. Pharmacological perturbation of proteostasis induces tumour regression in cooperation with gemcitabine in pre-clinical models of pancreatic cancer.

a, b, Waterfall plots (left) and box plots (right) of KPC^Δ/Δ GEMM-derived-allografts (GDAs) transplanted subcutaneously in NCr Nude mice assigned to a vehicle (n = 5), BIRB796 and SP600125 (n = 5), gemcitabine (n = 5), gemcitabine, BIRB796 and SP600125 (n = 7) (a); and vehicle (n = 7), AUY922 (n = 6), gemcitabine (n = 18), gemcitabine and AUY922 (n = 14) (b). V^D20 and V^D0, tumour volumes at day 20 and 0 of treatment, respectively. c, Schematic of experimental design for the establishment of PDX models of PDAC. There were two independent lines used, PATX53 and PATX50. d, Representative sections from tumour-bearing mice treated with AUY922 or vehicle. Scale bars: 100 μm. e, f, Bar graph showing the relative enrichment of SMARCB1^highGFP⁺ subpopulations upon treatment with AUY922 in orthotopic transplants of PDXs PATX53 (e) and PATX50 (f); n = 6 per group. g, h, Kaplan–Meier survival analysis of NOD SCID mice orthotopically transplanted with low-passage, PDAC PDX lines. Treatment with combined gemcitabine and AUY922 results in a significantly higher response rate and prolonged survival than treatment with monotherapies (PATX53, n = 7 per group; PATX50 vehicle, AUY992 and gemcitabine, n = 7 per group; PATX50, gemcitabine and AUY922, n = 14). Error bars denote mean ± s.d. of biological replicates (a, b, e, f). NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by unpaired two-tailed t-test (a, b, e, f) or Mantel–Cox log-rank test (g, h).