AB002. S002. Wild-type KRAS allele exerts its tumor-suppressive function through decreased Yap1 activation in pancreatic cancer

Abstract: KRAS is the most frequently mutated oncogene (about 95%) in pancreatic ductal adenocarcinoma (PDAC) and it has been shown to be essential for pancreatic tumor initiation and maintenance in both humans and mice. We have previously reported that the wild-type KRAS allele was selectively lost in both primary pancreatic tumors and metastases developed in a mouse model of PDAC, and the frequency of the wild-type loss increased from primary tumors to metastases in this mouse model and human pancreatic cancer cells. To interrogate the wild-type KRAS functions and its underlying mechanisms in pancreatic tumorigenesis, we restored the wild-type KRAS allele in a doxycycline (Dox) inducible manner in two pancreatic cancer cell lines that have undergone loss of the wild-type allele. We observed that the re-expression of the wild-type KRAS significantly reverse the proliferation, motility, and colony formation capabilities of these cancer cells in vitro. Furthermore, in vivo xenograft studies also demonstrated stalled tumor growth upon wild-type KRAS restoration. In contrast, overexpression of wild-type KRAS exerted no impact on pancreatic cancer cells that have retained the wild-type KRAS allele, suggesting that it’s the presence of the wild-type KRAS allele, not the dosage of total KRAS or the ratio of wild-type and mutant KRAS, that is vital in regulating tumor growth and metastasis. Lastly we examined several downstream signaling pathways associated with the regulation of KRAS and observed decreased Yap1 expression and nuclear translocation were induced by the restoration of the wild-type KRAS allele. Together these results ascribe the wild-type KRAS allele a tumor-suppressive role in the context of the mutant KRAS allele in pancreatic tumorigenesis via the inhibition of Yap1 activation.