| Project/Area Number |
16390363
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Osaka University |
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Principal Investigator |
NISHIDA Toshirou Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40263264)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIYAMA Yasuo Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (10049091)
HIROTA Seiichi Hyogo Medical School, Department of Clinical Pathology, Professor, 医学部, 教授 (50218856)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2004: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Keywords | Gastrointestinal stromal tumor / Molecular mechanism of resistance / KIT gene / PDGFRA gene / Molecular target therapy / Imatinib / Sunitinib / Allele / 二次耐性 / PDGFRα遺伝子 / 一次耐性 / 耐性 / ターゲット遺伝子 / KIT / PDGFR |
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| Research Abstract |
Resistance to the anticancer drugs is a determinant of the prognosis and QOL of patients with advanced cancer. There have been several mechanisms for drug resistance, however, molecular mechanisms of resistance to newly emerged target agents have not yet been elucidated. In this project, we have investigated molecular mechanisms of target agents using GIST resistant to imatinib and sunitinib as a model. Although imatinib has shown high activities on advanced GIST and improves the prognosis of GIST patients, half of patients suffered from appearance of imatinib-resistant GIST after 2 years treatment. We have focused analysis of a molecular mechanism on the KIT and PDGFRA genes and analyzed 25 patients (48 resistant lesions) of 42 patients who have imatinib-resistant GIST including 5 primary resistance and 37 secondary.
(1). Clinical features of resistant GIST :
CT revealed that 15 lesions showed a mass enlargement, 10 a nodule in a mass appearance, and only three lesions appeared as a new
… More
lesion. Some patients showed mixed type.
(2). Safety and therapeutic effects of surgery :
Twenty two patients with focal resistance or symptomatic systemic resistance underwent surgery and/or RFA. Surgery for resistant lesions is generally safe and acceptable with three minor complications. Although surgery for systemic resistance showed disappointed results without no prolongation of the prognosis compared to patients without surgery, surgery for focal progression conferred additional 6 months PFS. Patients with complete resection of resistant lesions had much better prognosis.
(3). Expression of KIT ＆ PDGFRA proteins and activations of downstream kinases :
All resistant lesions show viable spindle and/or epithelioid tumor cells which express KIT proteins in immunohistochemistory. Downstream kinases including AKT and MAPK are also re-activated.
(4). Acquired mutations in the KIT and/or PDGFRA genes :
twenty patients are endowed with acquired mutations in kinase domains of the KIT gene (11 in Ex13, 1 in Ex14, 10 in Ex17, 1 in Ex16+17 in addition to primary mutations). These mutations are in the same allele and resistant lesions showed clonal development. The other 5 patients had only primary mutations.
(5). Mutations and sunitinib resistance :
Six patients with imatinib-resistant GIST received sunitinib as a second-line therapy. Five patients showed primary resistance to sunitinib including three Ex 11+ Ex 17 mutations, Ex 9 +no additional mutation, and Ex 11+ Ex 13 mutation. The last patients had no increase in blood levels of sunitinib because of extended bowel resection. One patient with Ex 11+Ex 13 mutation showed PR to sunitinib, however, third mutation in Ex 17 allowed another development under sunitinib. Thus, second or third mutation in Ex 17 of the KIT gene conferred resistance to sunitinib.
In summary, target resistance with additional mutations in the KIT gene may be a main cause of secondary resistance to molecular targets agent of imatinib and sunitinib. Less
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