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Review
. 2024 Oct 1;23(10):1378-1388.
doi: 10.1158/1535-7163.MCT-23-0519.

KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma

Minh T Than  1   2 , Mark O'Hara  1   2 , Ben Z Stanger  1   2 , Kim A Reiss  1   2
Affiliations
Review

KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma

Minh T Than et al. Mol Cancer Ther. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFβ drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC.

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Figures

Figure 1.
Figure 1.
KRAS signaling and KRAS-directed therapy A. Schematic outline of KRAS gene-structure, highlighting hotspot mutations and farnesylated cysteine. B. Protein-interaction network evaluating high-confidence interactions with KRAS based on experimentally determined, curated, and co-expression databases. C. Outline of cell-intrinsic factors governed by KRAS signaling. Therapies undergoing clinical evaluation are denoted. D. Outline of cell-extrinsic factors governed by KRAS signaling. HVR – high variable region. CAFs – cancer-associated fibroblasts. MDSC – Myeloid-derived suppressor cells. TCR – T-cell receptor. GAP – GTPase activating protein. Created with BioRender.com
See this image and copyright information in PMC

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