鄭　佳　俞清翔　王　莉　王邦茂

天津醫(yī)科大學(xué)總醫(yī)院消化內(nèi)科(300052)

胃腸道間質(zhì)瘤伊馬替尼繼發(fā)耐藥治療的研究進(jìn)展*

鄭佳#俞清翔王莉王邦茂&

天津醫(yī)科大學(xué)總醫(yī)院消化內(nèi)科(300052)

Drug Therapy, Combination

胃腸道間質(zhì)瘤(gastrointestinal stromal tumors, GISTs)是最常見的胃腸道間葉源性腫瘤，研究發(fā)現(xiàn)KIT或血小板源性生長(zhǎng)因子受體α(PDGFRA)基因功能獲得性突變致酪氨酸激酶異常激活是GISTs發(fā)病的關(guān)鍵因素，針對(duì)突變基因的靶向治療藥物如酪氨酸激酶抑制劑(TKIs)伊馬替尼(imatinib)已成功應(yīng)用于臨床，在GISTs的治療中取得令人矚目的療效。然而，隨著治療時(shí)間的延長(zhǎng)，患者可對(duì)伊馬替尼產(chǎn)生繼發(fā)耐藥，從而極大影響治療效果，成為亟待解決的臨床難題。本文就GISTs伊馬替尼繼發(fā)耐藥治療的研究進(jìn)展作一綜述。

一、GISTs對(duì)伊馬替尼繼發(fā)耐藥的可能機(jī)制

GISTs對(duì)伊馬替尼耐藥分為原發(fā)耐藥和繼發(fā)耐藥，前者指應(yīng)用伊馬替尼治療無效，包括治療開始后疾病進(jìn)展(PD)或疾病穩(wěn)定(SD)<6個(gè)月；后者指在初始治療有效或獲得SD 6個(gè)月后發(fā)生PD[1]。以下為GISTs對(duì)伊馬替尼繼發(fā)耐藥的可能機(jī)制。

1. KIT/PDGFRA基因二次突變：多數(shù)研究認(rèn)為GISTs對(duì)伊馬替尼繼發(fā)耐藥與KIT/PDGFRA基因酪氨酸激酶結(jié)構(gòu)域二次突變密切相關(guān)[1-3]。一項(xiàng)meta分析顯示，與伊馬替尼繼發(fā)耐藥相關(guān)的KIT二次突變最常發(fā)生于外顯子17(54.5%)，其次為外顯子13(38.3%)和14(13.4%)[2]。Gao等[3]的研究顯示，伊馬替尼治療前KIT原發(fā)突變均發(fā)生于外顯子11或9，而治療后二次突變發(fā)生于外顯子17、13、18、14。

2. PTEN基因丟失：抑癌基因PTEN表達(dá)下調(diào)或丟失可致AKT過度活化而抵抗腫瘤細(xì)胞凋亡，進(jìn)而對(duì)TKIs產(chǎn)生耐藥[4]。伊馬替尼耐藥GIST細(xì)胞中的PTEN丟失主要為雜合子丟失[5-7]。Quattrone等[5]比較了伊馬替尼初治與繼發(fā)耐藥GIST患者的PTEN狀態(tài)，發(fā)現(xiàn)前者PTEN丟失率顯著低于后者(9%對(duì)39%)，約50%的繼發(fā)耐藥者PTEN蛋白低表達(dá)；體外實(shí)驗(yàn)顯示，以siRNA沉默GIST細(xì)胞的PTEN基因可上調(diào)PI3K/AKT/mTOR和MAPK信號(hào)通路活性。

3. 觸發(fā)GIST細(xì)胞進(jìn)入靜止期：伊馬替尼治療時(shí)，有相當(dāng)一部分GIST細(xì)胞并未發(fā)生凋亡，而是進(jìn)入靜止期，這些細(xì)胞雖已退出細(xì)胞分裂周期，但仍存活并具有代謝活性，可在逃逸伊馬替尼誘導(dǎo)的細(xì)胞凋亡后重新進(jìn)入細(xì)胞分裂周期，成為耐藥克隆的源頭，最終導(dǎo)致GISTs難治或復(fù)發(fā)[8]。有研究[9]發(fā)現(xiàn)伊馬替尼可通過調(diào)節(jié)APC/CDH1-SKP2-p27Kip1信號(hào)軸上調(diào)細(xì)胞周期蛋白依賴性激酶抑制劑p27Kip1，引起細(xì)胞周期蛋白A(cyclin A)表達(dá)下調(diào)，使GIST細(xì)胞退出S期而進(jìn)入靜止期。此外，Gupta等[10]發(fā)現(xiàn)伊馬替尼還可通過誘導(dǎo)自噬作用促使GIST細(xì)胞進(jìn)入靜止期。

二、伊馬替尼繼發(fā)耐藥GISTs的治療

1. 新型TKIs：GISTs繼發(fā)耐藥突變具有異質(zhì)性，特定位點(diǎn)突變抑制劑不能拮抗廣譜突變，多靶點(diǎn)TKIs成為當(dāng)前研究的熱點(diǎn)。氟馬替尼(flumatinib)是一種選擇性BCR-ABL/PDGFR/KIT抑制劑，可錨定于KIT的酪氨酸激酶結(jié)構(gòu)域，克服 活化環(huán)突變?nèi)鏒820G、N822K、Y823D、A829P等引起的GISTs耐藥，體內(nèi)實(shí)驗(yàn)顯示其對(duì)Y823D二次突變所致繼發(fā)耐藥細(xì)胞的抑制作用優(yōu)于伊馬替尼和舒尼替尼(sunitinib)[11]。瑞格非尼(regorafenib)對(duì)干細(xì)胞因子受體、PDGFR、成纖維細(xì)胞生長(zhǎng)因子受體(FGFR)、血管內(nèi)皮生長(zhǎng)因子受體(VEGFR)等均有抑制作用。相關(guān)Ⅲ期臨床試驗(yàn)顯示，對(duì)于伊馬替尼、舒尼替尼繼發(fā)耐藥的進(jìn)展期GIST患者(轉(zhuǎn)移性或不可切除)，瑞格非尼160 mg/d治療的中位無進(jìn)展生存期(PFS)顯著優(yōu)于安慰劑(4.8對(duì)0.9個(gè)月，HR: 0.27, 95% CI: 0.19~0.39,P<0.000 1)[12]。帕唑帕尼(pazopanib)可抑制KIT、VEGFR-1、-2、-3和PDGFR-α、-β。一項(xiàng)Ⅱ期臨床試驗(yàn)中，以帕唑帕尼800 mg/d治療25例伊馬替尼、舒尼替尼繼發(fā)耐藥的進(jìn)展期GIST患者，24周無進(jìn)展率[完全應(yīng)答(CR)+部分應(yīng)答(PR)+SD比率]僅為17%(95% CI: 4.5~37)，除1例患者外，其余均因PD或不能耐受而退出治療，中位PFS為1.9個(gè)月(95% CI: 1.6~5.2)，中位總生存期(OS)為10.7個(gè)月(95% CI: 3.9~NR)。上述結(jié)果表明，帕唑帕尼對(duì)伊馬替尼、舒尼替尼耐藥的進(jìn)展期GISTs療效不明顯[13]。

2. 伊馬替尼聯(lián)合下游通路靶向抑制劑：KIT/PDGFRA下游信號(hào)分子PI3K、AKT、mTOR等與GISTs對(duì)TKIs繼發(fā)耐藥密切相關(guān)，伊馬替尼與下游通路靶向抑制劑聯(lián)合應(yīng)用成為相關(guān)治療研究的新理念[14]。

①聯(lián)合mTOR抑制劑：GIST細(xì)胞裸鼠移植瘤模型研究[15]顯示，mTOR抑制劑依維莫司單用或與伊馬替尼聯(lián)用，對(duì)移植瘤生長(zhǎng)的抑制作用優(yōu)于單用伊馬替尼(腫瘤體積<0.5 cm3對(duì)>0.5 cm3)，并能顯著抑制腫瘤代謝，聯(lián)合用藥效果更佳。一項(xiàng)Ⅰ-Ⅱ期臨床試驗(yàn)評(píng)估了依維莫司聯(lián)合伊馬替尼對(duì)伊馬替尼耐藥GISTs的療效和安全性，Ⅱ期試驗(yàn)將患者分為僅伊馬替尼耐藥組和伊馬替尼以及其他TKIs耐藥組，予依維莫司2.5 mg/d+伊馬替尼600 mg/d治療，結(jié)果顯示兩組4個(gè)月時(shí)PFS率分別為17%和37%，中位PFS分別為1.9和3.5個(gè)月，中位OS分別為14.9和10.7個(gè)月，前一組SD和PD分別為36%和54%，后一組PR、SD和PD分別為2%、43%和32%，患者對(duì)聯(lián)合用藥耐受性良好[16]。

②聯(lián)合PI3K抑制劑：Floris等[7]以攜帶KIT不同位點(diǎn)突變的6種人GIST裸鼠移植瘤模型評(píng)價(jià)PI3K抑制劑GDC-0941與伊馬替尼聯(lián)用的抗腫瘤效應(yīng)，發(fā)現(xiàn)聯(lián)合組腫瘤負(fù)荷較初始值下降64%，效果顯著優(yōu)于兩者單用，腫瘤細(xì)胞增殖幾乎完全被抑制，細(xì)胞凋亡增加；在其中3個(gè)移植瘤模型中，聯(lián)合組停止給藥后腫瘤消退仍可維持，單用伊馬替尼則未見此效應(yīng)。上述結(jié)果表明單獨(dú)給藥只能部分抑制PI3K/AKT/mTOR信號(hào)通路，聯(lián)合用藥則可使之完全受抑。

③聯(lián)合PI3K/mTOR雙重抑制劑：體外實(shí)驗(yàn)顯示，PI3K/mTOR雙重抑制劑NVP-BEZ235與伊馬替尼聯(lián)用作用于GIST細(xì)胞，可發(fā)揮協(xié)同抗增殖作用；對(duì)于PTEN基因沉默或雙等位基因丟失的GIST細(xì)胞，NVP-BEZ235可部分降低AKT及其下游S6蛋白磷酸化水平，提示其對(duì)于此種GIST細(xì)胞的治療具有優(yōu)勢(shì)[6]。Van Looy等[17]通過伊馬替尼耐藥GIST細(xì)胞裸鼠移植瘤模型發(fā)現(xiàn)，單獨(dú)給予NVP-BEZ235只能穩(wěn)定腫瘤生長(zhǎng)，與伊馬替尼聯(lián)用才能完全抑制PI3K信號(hào)通路，使腫瘤顯著消退。

3. 較少依賴KIT/PDGFRA途徑的靶向抑制劑：KIT/PDGFRA及其下游信號(hào)分子已作為GISTs的治療靶點(diǎn)廣泛應(yīng)用于新藥研究，但迄今仍無某種藥物對(duì)所有類型的GISTs均有效。近年來，較少依賴KIT/PDGFRA途徑的靶向抑制劑日益受到關(guān)注。

①熱休克蛋白(HSP)抑制劑：HSP90作為分子伴侶可對(duì)細(xì)胞內(nèi)眾多信號(hào)蛋白如KIT、PDGFRA的構(gòu)象成熟和功能穩(wěn)定進(jìn)行調(diào)控，以防止其泛素化和降解，成為新興的抗GISTs藥物潛在作用靶點(diǎn)。Smyth等[18]的研究發(fā)現(xiàn)，HSP90抑制劑AT13387在伊馬替尼敏感和耐藥GIST細(xì)胞中均可耗竭KIT、AKT及其磷酸化形式p-KIT、p-AKT，從而抑制KIT信號(hào)通路，其抗GISTs活性在體內(nèi)外實(shí)驗(yàn)中得到驗(yàn)證；AT13387與伊馬替尼聯(lián)用對(duì)伊馬替尼耐藥GISTs的抑制作用優(yōu)于兩者單用。另有研究[19]顯示，除蛋白酶體依賴性降解途徑外，自噬作用亦部分參與了抑制HSP90誘導(dǎo)的KIT降解。

一項(xiàng)關(guān)于HSP90抑制劑BIIB021治療GISTs的 Ⅱ 期臨床試 驗(yàn)中，23例伊馬替尼、舒尼替尼耐藥患者接受BIIB021 600 mg 2次/周或400 mg 3次/周治療，22%的患者獲得代謝PR(mPR)，持續(xù)時(shí)間為25~138 d，未見明顯不良反應(yīng)[20]。37例進(jìn)展期GIST患者接受高效選擇性HSP90抑制劑IPI-504 90~500 mg/m22次/周×2周、間隔1周治療，SD為70%，mPR為38%，僅1例患者獲得PR，患者耐受性良好[21]。

②極光激酶(aurora kinase)抑制劑：極光激酶在有絲分裂中起關(guān)鍵作用，與p53、p21、Chfr等抑癌基因共同參與腫瘤發(fā)生。研究[22-23]證實(shí)極光激酶A高表達(dá)是GISTs預(yù)后不良[低無復(fù)發(fā)生存期(RFS)、PFS和OS]的獨(dú)立危險(xiǎn)因素。Yeh等[23]發(fā)現(xiàn)極光激酶A抑制劑MLN8237對(duì)伊馬替尼耐藥和敏感GIST細(xì)胞均有生長(zhǎng)抑制作用，其機(jī)制涉及上調(diào)p21和p53、誘導(dǎo)細(xì)胞周期G2/M期阻滯和誘導(dǎo)細(xì)胞衰老、凋亡，如與伊馬替尼聯(lián)用，可協(xié)同發(fā)揮細(xì)胞毒作用。

③組蛋白去乙?；敢种苿?HDACI)：組蛋白去乙?；甘蔷S持染色體的基本組成單位核小體中組蛋白乙?；胶獾年P(guān)鍵酶之一。伊馬替尼對(duì)GIST細(xì)胞的促凋亡作用部分是由上調(diào)可溶性組蛋白H2AX致染色質(zhì)異常積聚和轉(zhuǎn)錄阻滯所介導(dǎo)[24]，提示抑制H2AX去乙?；赡芘c伊馬替尼產(chǎn)生協(xié)同作用。攜帶KIT不同位點(diǎn)突變?nèi)薌IST細(xì)胞或組織裸鼠移植瘤模型研究[25]顯示，與對(duì)照組相比，HDACI帕比司他能使腫瘤縮小25%，組織學(xué)檢查可見壞死、出血、纖維化、黏液樣變性等改變，細(xì)胞凋亡顯著，分裂活性降低，如與伊馬替尼聯(lián)用，上述效應(yīng)更為突出。Mühlenberg等[26]報(bào)道HDACI僅對(duì)KIT陽(yáng)性GIST細(xì)胞有增殖抑制作用，表明KIT為其作用靶點(diǎn)，其機(jī)制包括下調(diào)KIT mRNA轉(zhuǎn)錄、導(dǎo)致HSP90乙?；蓴_其KIT伴侶活性。一項(xiàng) Ⅰ 期臨床試驗(yàn)納入12例伊馬替尼繼發(fā)耐藥轉(zhuǎn)移性GIST患者，伊馬替尼400 mg/d治療1周后開始加用帕比司他，1例患者獲得mPR，7例為mSD，3例為PD[27]。

4. 誘導(dǎo)靜止期GIST細(xì)胞凋亡：DREAM復(fù)合體在伊馬替尼誘導(dǎo)GIST細(xì)胞進(jìn)入靜止期中起關(guān)鍵作用，通過敲除DREAM復(fù)合體的各組成亞基或以藥物抑制DREAM調(diào)節(jié)激酶DYRK1A或其靶分子LIN52以干擾DREAM復(fù)合體形成，可增強(qiáng)伊馬替尼的抗GISTs活性，促進(jìn)腫瘤細(xì)胞凋亡[28-29]。鑒于伊馬替尼可通過誘導(dǎo)自噬作用促使GIST細(xì)胞進(jìn)入靜止期，抑制自噬亦可能有助于GISTs的治療。體內(nèi)外實(shí)驗(yàn)均顯示以siRNA沉默自噬相關(guān)基因可顯著下調(diào)自噬體表達(dá)，抑制GIST細(xì)胞進(jìn)入靜止期，阻止繼發(fā)耐藥發(fā)生，增強(qiáng)伊馬替尼的細(xì)胞毒作用[10]。

5. 其他：Edris等[30]發(fā)現(xiàn)，在伊馬替尼耐藥和敏感人GIST細(xì)胞及其移植瘤模型中，抗KIT單克隆抗體SR1均可抑制腫瘤細(xì)胞生長(zhǎng)，其機(jī)制除下調(diào)KIT表達(dá)外，尚涉及增強(qiáng)免疫細(xì)胞的腫瘤清除能力。有研究[31]探討了不同TKIs對(duì)KIT活化環(huán)二次突變GIST細(xì)胞的作用，結(jié)果顯示舒尼替尼對(duì)外顯子13、14二次突變細(xì)胞的抑制作用強(qiáng)于外顯子17二次突變細(xì)胞；而尼羅替尼(nilotinib)和索拉非尼(sorafenib)與伊馬替尼、舒尼替尼和達(dá)沙替尼(dasatinib)相比，能顯著抑制外顯子17二次突變細(xì)胞的KIT磷酸化。上述發(fā)現(xiàn)提示，對(duì)于伊馬替尼繼發(fā)耐藥GIST患者，檢測(cè)基因突變狀態(tài)以選擇合適的TKIs可能有助于GISTs的治療。

三、結(jié)語與展望

GISTs耐藥機(jī)制的逐漸闡明為其治療提供了重要依據(jù)。盡管分子靶向藥物如各種新型TKIs、KIT分子伴侶抑制劑、極光激酶抑制劑、HDACI以及聯(lián)合應(yīng)用下游信號(hào)分子抑制劑、誘導(dǎo)靜止期GIST細(xì)胞凋亡等方面的研究已取得一定進(jìn)展，但其用于治療伊馬替尼繼發(fā)耐藥的有效性和安全性尚需進(jìn)一步評(píng)估以及更多設(shè)計(jì)良好的臨床試驗(yàn)加以驗(yàn)證。鑒于KIT/PDGFRA基因突變的異質(zhì)性，突變位點(diǎn)的檢測(cè)有助于選擇針對(duì)性的治療藥物。根據(jù)基因型裁剪的治療方案是實(shí)現(xiàn)GISTs個(gè)體化治療的新挑戰(zhàn)，只有實(shí)現(xiàn)以分子機(jī)制為基礎(chǔ)的個(gè)體化治療，才可能實(shí)現(xiàn)GISTs的長(zhǎng)期緩解和最終治愈。

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(2014-10-31收稿；2014-12-28修回)

摘要酪氨酸激酶抑制劑伊馬替尼在胃腸道間質(zhì)瘤(GISTs)的治療中已取得令人矚目的療效，然而伊馬替尼繼發(fā)耐藥的出現(xiàn)成為亟待解決的臨床難題。GISTs對(duì)伊馬替尼繼發(fā)耐藥的可能機(jī)制包括KIT/PDGFRA基因二次突變、PTEN基因丟失、觸發(fā)GIST細(xì)胞進(jìn)入靜止期等。針對(duì)上述耐藥機(jī)制，目前已提出新型酪氨酸激酶抑制劑、聯(lián)合應(yīng)用下游通路靶向抑制劑、較少依賴KIT/PDGFRA途徑的靶向抑制劑(KIT分子伴侶抑制劑、極光激酶抑制劑等)、誘導(dǎo)靜止期GIST細(xì)胞凋亡等解決伊馬替尼繼發(fā)耐藥的策略，本文就相關(guān)研究進(jìn)展作一綜述。

關(guān)鍵詞胃腸道間質(zhì)瘤；伊馬替尼；繼發(fā)耐藥；分子靶向治療；藥物療法，聯(lián)合

Advances in Management of Gastrointestinal Stromal Tumors with Secondary Resistance to ImatinibZHENGJia,YUQingxiang,WANGLi,WANGBangmao.DepartmentofGastroenterologyandHepatology,TianjinGeneralHospital,TianjinMedicalUniversity,Tianjin(300052)

Correspondence to: WANG Bangmao, Email: gi.tmuh@sohu.com

AbstractThe use of tyrosine kinase inhibitor imatinib in treatment of gastrointestinal stromal tumors (GISTs) has achieved a dramatic therapeutic efficacy. However, secondary imatinib resistance emerged as a clinical problem needs to be solved urgently. The underlying mechanisms of GISTs secondary resistance to imatinib may be related with secondary mutations of KIT/PDGFRA genes, loss of PTEN gene and induction of cellular quiescence. This resulted in the adoption of new therapeutic strategies such as novel tyrosine kinase inhibitors, combined use of imatinib with downstream signaling inhibitors, KIT/PDGFRA independent targeted inhibitors such as KIT chaperone inhibitors and aurora kinase inhibitors, as well as inducing apoptosis in quiescent GIST cells. In this article, the above-mentioned issues were summarized.

Key wordsGastrointestinal Stromal Tumors;Imatinib;Secondary Resistance;Molecular Targeted Therapy;

通信作者&本文，Email: gi.tmuh@sohu.com

DOI:*基金項(xiàng)目：國(guó)家自然科學(xué)基金青年科學(xué)基金項(xiàng)目(81000157);#Email: zhengjia2255@126.com