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Figure 1 from KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition

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posted on 2025-01-15, 08:21 authored by Sigrid K. Fey, Arafath K. Najumudeen, Dale M. Watt, Laura M. Millett, Catriona A. Ford, Kathryn Gilroy, Rosalin J. Simpson, Kathy McLay, Rosanna Upstill-Goddard, David Chang, William Clark, Colin Nixon, Joanna L. Birch, Simon T. Barry, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom

Loss of WT Kras increases PanIN formation in the presence of oncogenic Kras. A, Kaplan–Meier survival curve for human patients with PDAC with KRAS alleles balanced and KRAS alleles imbalanced. KRAS balanced, n = 47; KRAS imbalanced, n = 32. *, P = 0.029, log-rank (Mantel–Cox) test. B, Proportion of human patients with pancreatic cancer with KRAS alleles balanced (59.5%) and KRAS alleles imbalanced (40.5%), from A. C, Schematic representing generation of KC KrasG12D/fl mice. D, Representative hematoxylin and eosin (H&E) images of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age, representative of six mice per group. Scale bar, 200 μm. E, Quantification and grading of PanINs from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age from one whole hematoxylin and eosin section per mouse (n = 6 per group), represented by D. Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. **, P < 0.01; one-way Mann–Whitney U test. F, Quantification of the area of ADM per mm2 pancreas over one whole hematoxylin and eosin section from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age (n = 6 per group). Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. **, P < 0.0011; one-way Mann–Whitney U test. G, Left, representative IHC images of pERK1/2 of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age. Representative of six mice per group. Scale bar, 200 μm. Right, bar graphs showing quantification of pERK1/2-positive cells of the pancreatic epithelium of KC KrasG12D/+ and KC KrasG12D/fl mice sampled at day 42 (KC KrasG12D/+, n = 6; KC KrasG12D/fl, n = 6). Data are the mean ± SEM. *, P = 0.0325; one-way Mann–Whitney U test. H, Left, representative images of ISH of Dusp5 and Dusp6 of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age. Representative of six mice per group. Scale bar, 200 μm. Right, quantification of Dusp5 and Dusp6 ISH staining of pancreatic lesions (PanINs) of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age (KC KrasG12D/+, n = 6; KC KrasG12D/fl, n = 6). Data are the mean ± SEM. **, P = 0.0011 (Dusp5); **, P = 0.0022 (Dusp6); one-way Mann–Whitney U test. Cre, Cre recombinase; loxP, Cre-loxP recombination site.

Funding

Cancer Research UK (CRUK)

HORIZON EUROPE European Research Council (ERC)

Pancreatic Cancer UK (PCUK)

Medical Research Council (MRC)

History

ARTICLE ABSTRACT

Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. Whereas the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type (WT) KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modeling of pancreatic cancer, we demonstrated that WT KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of WT Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of WT KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of WT Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of WT KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of WT KRAS in both tumor progression and therapeutic response in pancreatic cancer.Significance: KRAS allelic status impacts pancreatic cancer progression and has the potential to guide effective treatment in a substantial subset of patients.