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Figure 2 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

Early intervention with AZD6244 reduces PanIN burden in KrasG12D/fl mice. A, Experimental schematic. KC KrasG12D/fl were treated from day 42 for 28 days with vehicle or AZD6244 and sampled at day 70. B, Representative hematoxylin and eosin (H&E), pERK1/2, and Ki67 IHC images from pancreata of KC KrasG12D/fl mice at 70 days of age following treatment with vehicle or AZD6244 as indicated for 28 days. Representative of four mice per group. Scale bar, 200 μm. C, Quantification and grading of PanINs from pancreata of KC KrasG12D/+ and KC KrasG12D/fl mice treated with vehicle or AZD6244 from 42 to 70 days of age, scored from whole hematoxylin and eosin sections (n = 4 per group). Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. D, Quantification of the area of ADM per mm2 pancreas over one whole hematoxyly and eosin section from pancreata of KC KrasG12D/fl mice treated as indicated from day 42 for 28 days (n = 4 per group). Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. Comparison by one-way Mann–Whitney U test. E, Representative images of c-MYC IHC and Dusp6 ISH of KC KrasG12D/fl mice treated with vehicle or AZD6244 as indicated from day 42 for 28 days. Representative of four mice per group. Scale bar, 200 μm.

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.