KRAS: the Achilles’ heel of pancreas cancer biology

The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered "undruggable," KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.