Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese
- PDF / 439,004 Bytes
- 7 Pages / 595.276 x 790.866 pts Page_size
- 101 Downloads / 148 Views
ORIGINAL PAPER
Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors Jing Gao • Ye Tian • Jian Li • Naiping Sun Jiajia Yuan • Lin Shen
•
Received: 27 December 2012 / Accepted: 22 February 2013 Ó Springer Science+Business Media New York 2013
Abstract The aim of this study was to investigate the associations between secondary mutations of c-KIT/ PDGFRa and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRa (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRa mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P \ 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether Jing Gao and Ye Tian contributed equally to this work. J. Gao Y. Tian J. Li N. Sun J. Yuan L. Shen (&) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China e-mail: [email protected]
secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated. Keywords c-KIT Secondary mutation Acquired resistance Imatinib Sunitinib
Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system generated from Cajal cells or its precursor [1]. Most GISTs are accompanied with oncogenic mutations of c-KIT or platelet-derived growth factor receptor alpha (PDGFRa). About 90 % mutations occur in c-KIT, commonly observed in exons 11 and 9, and rarely in other exons of c-KIT. Only about 5 % patients harbor PDGFRa mutations. The mutations of c-KIT and PDGFRa are mutually exclusive [2–5]. Imatinib mesylate is an oral small molecular inhibitor of tyrosine kinases, which targets c-KIT, PDGFRa, and other tyrosine kinases [6,
Data Loading...
