KRAS mutation in pancreatic cancer

Abstract

Pancreatic cancer is a recalcitrant cancer with one of the lowest 5-year survival rates. A hallmark of pancreatic cancer is the prevalence of oncogenic mutation in the KRAS gene. The KRAS oncogene plays a critical role in the initiation and maintenance of pancreatic tumors and its signaling network represents a major target for therapeutic intervention. A number of inhibitors have been developed against kinase effectors in various Ras signaling pathways. Their clinical activity, however, has been disappointing thus far. More recently, covalent inhibitors targeting the KRAS^G12C oncoprotein have been developed. These inhibitors showed promising activity in KRAS^G12C mutant pancreatic cancer in early clinical trials. This review will present an updated summary of our understanding of mutant KRAS function in pancreatic cancer and discuss therapeutic strategies that target oncogenic KRAS signaling in this disease.

Keywords: G12C; KRAS; MAPK pathway; Pancreatic cancer; Targeted therapy.

Figure 1.

Common oncogenic mutations in the development of pancreatic cancer. PDAC, pancreatic ductal adenocarcinoma; PanIN, pancreatic intraepithelial neoplasia.

Figure 2.

A simplified schematic of the Ras signaling network with major canonical effector pathways shown. Oncogenic mutation in Ras locks it in the GTP-bound, active form, therefore resulting in constitutive signaling to downstream pathways. GEFs, guanine nucleotide exchange factors; GAPs, GTPase-activating proteins; WT, wild type.

Figure 3.

Distribution of KRAS mutations in pancreatic cancer. The analysis was done using publicly available data from the cBioPortal database (48, 49) that includes 665 KRAS mutant tumor samples from four large scale pancreatic cancer studies (–53).

Figure 4.

The sensitivity of KRAS mutant and WT cell lines to CRISPR-mediated KRAS knockout, to the MEK inhibitor selumetinib and to the ERK inhibitor SCH772984. The analysis was done using publicly available data from the DepMap database. For the KRAS CRISPR data, normalized sensitivity score (CERES) was used (65). Within each tumor type, KRAS mutant cells are more sensitive to KRAS knockout than KRAS WT cells (*** p < 0.001). For the drug sensitivity data, normalized area under the curve (AUC) data was used for both selumetinib (CDT² dataset) and SCH772984 (Sanger GDSC2 dataset) (69, 70). Within each tumor type, KRAS mutant cells are not significantly (n.s.) more sensitive to the inhibitor than KRAS WT cells, with the exception of NSCLC cells to selumetinib (* p = 0.01). Each data point represents an individual cell line. PDAC, pancreatic ductal adenocarcinoma; CRC, colorectal adenocarcinoma; Chol, cholangiocarcinoma; Gas, gastric adenocarcinoma; NSCLC, non-small cell lung cancer; a.u. arbitrary units.