KRAS: the Achilles’ heel of pancreas cancer biology
Kristina Drizyte-Miller, … , Adrienne D. Cox, Channing J. Der
Kristina Drizyte-Miller, … , Adrienne D. Cox, Channing J. Der
Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e191939. https://doi.org/10.1172/JCI191939.
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Review Series

KRAS: the Achilles’ heel of pancreas cancer biology

Abstract

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.

Authors

Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der

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Figure 1

KRAS mutations in PDAC.

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KRAS mutations in PDAC. (A) Schematic illustrating pancreatic ductal ad...
(A) Schematic illustrating pancreatic ductal adenocarcinoma (PDAC) pathogenesis and progression (adapted from ref. 176 with permission from Springer Nature Limited, which retains the rights to the reference image). Mutations in KRAS oncogene are the initiating step in PDAC development, and they induce transformation of normal pancreas epithelium to low-grade pancreatic intraepithelial neoplasia (PanIN). Progression from low-grade PanINs to high-grade PanINs and eventually invasive PDAC is caused by loss-of-function mutations in CDKN2A, TP53, and SMAD4 tumor suppressor genes. The severity of disease is also associated with increased KRASmut copy numbers. (B) KRAS mutation frequencies in PDAC. Data were compiled from the cBioPortal GENIE Cohort v17.0 database (48) from 7,407 patients with PDAC. Of the three RAS isoforms, KRAS is the predominantly mutated isoform, with NRAS and HRAS mutations accounting for <1% of PDAC cases. Of the three mutational hot spots, G12X mutations are most common in PDAC, with G12D, G12V, and G12R representing the predominant amino acid mutations at this position. G13X mutations are rare in PDAC and comprise less than 1% of KRAS mutations. Q61X mutations are also uncommon, accounting for 7% of KRAS point mutations, with Q61H representing the predominant mutation. The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of the authors.