Details

Autor(en) / Beteiligte

• Lee, Mi Rim
• Woo, Sang Myung
• Kim, Min Kyeong
• Han, Sung‐Sik
• Park, Sang‐Jae
• Lee, Woo Jin
• Lee, Dong‐eun
• Choi, Sun Il
• Choi, Wonyoung
• Yoon, Kyong‐Ah
• Chun, Jung Won
• Kim, Yun‐Hee
• Kong, Sun‐Young

Titel

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

Ist Teil von

• Cancer science, 2024-04, Vol.115 (4), p.1283-1295

Ort / Verlag

England: John Wiley and Sons Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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. We explored the potential of screening KRAS mutations in plasma circulating tumor deoxyribonucleic acid (ctDNA) to drive therapeutic approaches for pancreatic ductal adenocarcinoma (PDAC). KRAS mutation in ctDNA had a higher predicitive rate than DNA in tumor, and this was accomplished by investigating the effect of KRAS G12C inhibitor in preclinical models such as patient‐derived xenografts (PDX) and patient‐derived organoids (PDO). The monitoring of KRAS mutation in plasma ctDNA may guide a direction for targeted therapy of PDAC.