2. Academic Validation
  3. Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer

Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer

  • Cancer Sci. 2024 Feb 13. doi: 10.1111/cas.16104.
Mi Rim Lee 1 2,  Sang Myung Woo 1 3 4,  Min Kyeong Kim 5,  Sung-Sik Han 1 3,  Sang-Jae Park 3,  Woo Jin Lee 3 6,  Dong-Eun Lee 7,  Sun Il Choi 1 2 8,  Wonyoung Choi 1 9 10,  Kyong-Ah Yoon 11,  Jung Won Chun 3 6,  Yun-Hee Kim 1 2,  Sun-Young Kong 1 5 12
Affiliations

Affiliations

  • 1 Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Korea.
  • 2 Molecular Imaging Branch, Division of Convergence Technology, Research Institute of National Cancer Center, Goyang, Korea.
  • 3 Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer Center, Goyang, Korea.
  • 4 Immuno-Oncology Branch, Division of Rare and Refractory Center, Research Institute of National Cancer Center, Goyang, Korea.
  • 5 Targeted Therapy Branch, Division of Rare and Refractory Center, Research Institute of National Cancer Center, Goyang, Korea.
  • 6 Interventional Medicine Branch, Division of Clinical Research, Research Institute of National Cancer Center, Goyang, Korea.
  • 7 Biostatistics Collaboration Team, Research Core Center, National Cancer Center, Goyang, Korea.
  • 8 Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng, Henan, China.
  • 9 Center for Clinical Trials, Hospital, National Cancer Center, Goyang, Korea.
  • 10 Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute of National Cancer Center, Goyang, Korea.
  • 11 College of Veterinary Medicine, Konkuk University, Seoul, Korea.
  • 12 Department of Laboratory Medicine, Hospital, National Cancer Center, Goyang, Korea.
PMID: 38348576 DOI: 10.1111/cas.16104
Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived Organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

Keywords

KRAS; KRAS G12C inhibitor; circulating tumor DNA; pancreatic ductal adenocarcinoma; patient-derived organoid.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C Inhibitor
    Ras