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Molecular mechanisms of drug resistance in cancer.-GIST resistant to imatinib as a model-

癌症耐药的分子机制。-GIST对伊马替尼耐药的模型-

基本信息

批准号：
16390363
负责人：
NISHIDA Toshirou
金额：
$ 8.96万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390363/
关键词：
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

项目摘要

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

对抗癌药物的耐药性是决定晚期癌症患者预后和生活质量的决定因素。耐药的机制有多种，然而，对新出现的靶向药物的耐药的分子机制尚未阐明。本课题以伊马替尼和舒尼替尼耐药的GIST为模型，研究靶向药物的分子机制。尽管伊马替尼对晚期GIST表现出较高的活性，并改善了GIST患者的预后，但半数患者在治疗2年后出现伊马替尼耐药的GIST。我们重点分析了KIT和PDGFRA基因的分子机制，并分析了42例伊马替尼耐药GIST患者中的25例（48个耐药病灶），其中包括5例原发性耐药和37例继发性耐药。（一）.耐药GIST的临床特点：CT显示15个病灶呈肿块样增大，10个病灶呈肿块样结节，仅3个病灶呈新病灶。 ...更多信息损伤。部分患者表现为混合型。（二）、手术的安全性和治疗效果：22例局灶性阻力或症状性全身阻力患者接受了手术和/或RFA。手术治疗耐药病变通常是安全和可接受的，有三个轻微的并发症。尽管与未手术的患者相比，针对全身抵抗的手术显示出令人失望的结果，且未延长预后，但针对局灶性进展的手术提供了额外的6个月PFS。完全切除耐药病灶的患者预后较好。（三）、KIT和PDGFRA蛋白的表达和下游激酶的激活：所有耐药病变均显示出活的梭形和/或上皮样肿瘤细胞，其在细胞化学中表达KIT蛋白。下游激酶包括AKT和MAPK也被重新激活。（四）、KIT和/或PDGFRA基因中的获得性突变：20名患者在KIT基因的激酶结构域中具有获得性突变（除原发突变外，Ex 13中11名，Ex 14中1名，Ex 17中10名，Ex 16 +17中1名）。这些突变位于同一等位基因上，耐药病灶呈克隆发展。其他5例患者仅发生原发性突变。（五）、突变和舒尼替尼耐药：6例伊马替尼耐药GIST患者接受舒尼替尼作为二线治疗。5例患者显示对舒尼替尼的原发性耐药，包括3个Ex 11+ Ex 17突变、Ex 9 +无其他突变和Ex 11+ Ex 13突变。最后一名患者由于延长肠切除术而没有增加舒尼替尼的血液水平。一名具有Ex 11+Ex 13突变的患者显示对舒尼替尼的PR，然而，Ex 17中的第三突变允许在舒尼替尼下的另一种发展。因此，KIT基因Ex 17的第二次或第三次突变赋予了对舒尼替尼的耐药。综上所述，KIT基因额外突变的靶向耐药可能是对伊马替尼和舒尼替尼分子靶向药物产生继发性耐药的主要原因。少