The Long, Remarkable History of KRAS and Pancreatic Cancer: From Gene Discovery to Successful Therapeutic Targeting.

Inhibitors of the KRAS protein have recently been reported to significantly improve the survival of patients with pancreatic cancer, bringing hope where once there was none. It is therefore timely, at this remarkable inflection point, that we review the long history of discoveries, many of them made by pathologists, that constructed this hope. Looking back, almost 20 years passed between Kirsten and Mayer's 1967 report of a transforming "murine sarcoma virus" and the first reports, in the mid-1980s, of somatic KRAS gene mutations in human pancreatic ductal adenocarcinomas (pancreatic cancers). The decades that followed saw confirmation of the remarkably high prevalence of these mutations in pancreatic cancer and the characterization of the timing of these mutations in precursor lesions, pancreatic intraepithelial neoplasms and intraductal papillary mucinous neoplasms. The demonstration in 2003 by Tuveson et al that the introduction of mutant KrasG12D into the mouse pancreas leads to the development of pancreatic cancer and its precursor lesions helped solidify the causal role for KRAS as an early driver of pancreatic tumorigenesis. In the years that followed, the high prevalence of somatic KRAS mutations in precursor lesions and in pancreatic cancer was used as a foundation for the development of new approaches to classify cyst type in the pancreas and to detect pancreatic cancer earlier. In 2013, Shokat et al reported the successful direct chemical inhibition of mutant (KRASG12C) KRAS. The undruggable became druggable. There are now over 50 agents, small molecules, and vaccines targeting mutant KRAS in clinical trials, and early reports include a near doubling of survival for patients with advanced disease. This story highlights the long arc of science: although decades may separate a fundamental discovery from improvements in inpatient care, research saves lives.