慢性粒細胞白血病對伊馬替尼的耐藥機制研究進展

苗圣超 糜堅青

(上海交通大學醫(yī)學院附屬瑞金醫(yī)院血液科，上海 200025)

慢性粒細胞白血病(chronic myeloid leukemia，CML)是一種造血干細胞克隆增殖性疾病。95%以上的CML患者可檢測到特征性的費城(Ph)染色體和bcr-abl融合基因。該融合基因編碼一種具有酪氨酸激酶活性的蛋白，通過一系列復雜的細胞信號轉(zhuǎn)導途徑，使造血干細胞發(fā)生異常轉(zhuǎn)化而導致CML的發(fā)生[1]。伊馬替尼是治療CML的一線藥物，但隨著伊馬替尼的臨床應用范圍的擴大和時間的推移，耐藥現(xiàn)象逐漸顯現(xiàn)。

1 CML發(fā)病機制

95%以上的CML患者體內(nèi)可檢測到異常的Ph染色體，它是由9號染色體和22號染色體的長臂相互易位構成[t(9；22)(q34；q11)]。這種易位使位于9號染色體長臂(9q34)上的原癌基因abl和位于22號染色體長臂(22q11)上的bcr基因重新組合，從而形成bcr-abl融合基因。形成融合基因時，abl基因的斷裂點較固定，而bcr基因的斷裂點不一，常集中在m-bcr、M-bcr和μ-bcr 3個區(qū)域[2]。從而產(chǎn)生不同形式的bcr-abl融合基因，進而表達分子質(zhì)量為190 kD、210 kD、230 kD的融合蛋白P190、P210、P230。P190主要見于急性淋巴細胞白血病(acute lymphoblastic leukemia，ALL)，P230主要見于慢性中性粒細胞白血病(chronic neutrophilic leukemia，CNL)，P210主要見于CML。CML相關的bcr基因斷裂點常位于M-bcr，形成的融合基因轉(zhuǎn)錄產(chǎn)物為b2a2或b3a2，進而表達融合蛋白P210[3]。P210融合蛋白在CML的發(fā)病中起關鍵作用，它具有異常增強的酪氨酸激酶活性，與三磷酸腺苷(ATP)結合后激活Ras/MAPK、PI3K/Akt、STAT5等通路，導致細胞惡性增生、凋亡障礙，使骨髓基質(zhì)細胞黏性下降，造成造血干細胞的惡性轉(zhuǎn)化，進而導致CML的發(fā)生[4]。

2 伊馬替尼作用機制

伊馬替尼是人工合成的酪氨酸激酶抑制劑，用于治療Ph染色體陽性的CML急性期、加速期或α-干擾素治療失敗的慢性期患者。目前，伊馬替尼已成為治療CML的一線藥物，它通過競爭性抑制ATP與酪氨酸激酶催化中心的結合，阻斷酪氨酸激酶的活化，進而干擾CML細胞生存，達到治療的目的[5-6]。

3 伊馬替尼的耐藥機制

伊馬替尼的耐藥特點呈現(xiàn)多樣化，常見的有以下幾種：(1)一些新診斷CML的患者對伊馬替尼不敏感，不能達到完全血液學緩解，另外，20%～25%患者不能達到完全細胞遺傳學緩解[7]；(2)95%以上的CML患者應用伊馬替尼后，雖然已經(jīng)獲得完全細胞遺傳學緩解，但體內(nèi)仍殘留BCR-ABL陽性的細胞[8]，這些細胞對伊馬替尼耐藥，成為疾病惡化的誘因；(3)20%～25%的CML患者，起初對伊馬替尼敏感，但在治療過程中會很快產(chǎn)生耐藥；(4)伊馬替尼對大部分CML慢性期患者有效，但對加速期和急性期患者不敏感，容易出現(xiàn)耐藥[9]。伊馬替尼的耐藥機制可分為BCR-ABL依賴的耐藥機制和BCR-ABL非依賴的耐藥機制。

3.1 BCR-ABL依賴的耐藥機制

3.1.1 點突變 BCR-ABL點突變是伊馬替尼耐藥的主要機制，約50%耐藥患者可檢測到點突變[10-11]。迄今為止，已發(fā)現(xiàn)90多個不同的點突變與伊馬替尼耐藥有關[12-13]。突變的BCR-ABL激酶由于氨基酸發(fā)生改變，引起激酶結構的改變，直接阻斷或間接干擾了伊馬替尼與BCR-ABL激酶的結合，從而導致耐藥的產(chǎn)生[14]。根據(jù)BCR-ABL激酶空間結構，點突變可以發(fā)生在以下位置：ATP結合環(huán)(P-環(huán)，第244～255個氨基酸殘基)、激活環(huán)(A-環(huán)，第381～402個氨基酸殘基)、催化域(第350～363個氨基酸殘基)、直接與伊馬替尼結合的殘基[15]。BCR-ABL突變影響CML患者對伊馬替尼的敏感性，且不同的突變類型和位置引起的耐藥程度不同[16-18]。其中，T315I突變和P-環(huán)突變是最常見的突變[11,19]，占所有突變類型的85%。T315I突變是第1個被報道的ABL激酶點突變[20]。BCR-ABL激酶第315位的蘇氨酸(T)通過氫鍵直接與伊馬替尼結合，然而，當蘇氨酸突變?yōu)楫惲涟彼?I)時，異亮氨酸由于缺乏氫鍵而不能與伊馬替尼結合[21]，同時異亮氨酸龐大的體積增加了伊馬替尼的空間位阻[22]，從而阻斷了伊馬替尼與BCR-ABL激酶的結合。P-環(huán)突變主要發(fā)生于加速期和急性期的CML患者，與其他位置的突變相比，發(fā)生P-環(huán)突變的CML患者將更迅速地進展至加速期，且預后更差[18]。

3.1.2 移碼突變 大多數(shù)已知的BCR-ABL突變是點突變，移碼突變非常罕見。移碼突變包括插入突變和缺失突變2種形式。2012年Park等[23]報告，在2例韓國CML患者中發(fā)現(xiàn)了1個新的插入突變，該突變是由BCR-ABL激酶域中插入35個堿基引起的(p.Cys475Tyrfs * 11)。此外，他們發(fā)現(xiàn)，與點突變相比，移碼突變引起的耐藥程度可能更嚴重。

針對BCR-ABL突變，第2代酪氨酸激酶抑制劑如達沙替尼、尼羅替尼應運而生。第2代酪氨酸激酶抑制劑對大部分的BCR-ABL突變有效，但是對一部分BCR-ABL突變卻不敏感，尤其是T315I突變。長久以來，因為缺乏有效的治療方法，T315I突變成為臨床的難題。Cassuto等[24]證實，第3代酪氨酸激酶抑制劑帕納替尼對所有突變類型耐藥的CML細胞株均有效，尤其是T315I突變。2012年12月14日，帕納替尼獲美國FDA批準上市，為酪氨酸激酶抑制劑耐藥的CML患者帶來了福音。

3.1.3 BCR-ABL蛋白高表達 BCR-ABL高表達的發(fā)生機制仍不明確。Gorre等[20]發(fā)現(xiàn)，11例獲得性耐藥患者中有3例體內(nèi)可檢測到bcr-abl基因的擴增。但是，在一些耐藥的患者中，雖然BCR-ABL蛋白是高表達的，卻未發(fā)現(xiàn)bcr-abl基因擴增，說明除了bcr-abl基因擴增外，BCR-ABL高表達可能還與其他機制有關[25-26]。此外，Barnes等[27]發(fā)現(xiàn)，CD34+的CML細胞中BCR-ABL表達水平的不同可能使其對伊馬替尼反應的程度與持續(xù)時間不同，如在加速期BCR-ABL表達相對較高的細胞可較快出現(xiàn)伊馬替尼耐藥；研究[28-29]發(fā)現(xiàn)，伊馬替尼無法徹底清除原始細胞(lin-CD34+CD38-)，可能與BCR-ABL蛋白在這些細胞中表達水平較高有關。Kumari等[30]發(fā)現(xiàn)，BCR-ABL的高表達能催化BCR-ABL突變和伊馬替尼耐藥的發(fā)生。

3.2 BCR-ABL非依賴的耐藥機制

3.2.1 藥物流入和流出 可能與伊馬替尼耐藥有關的外排性轉(zhuǎn)運蛋白主要包括P-糖蛋白(P-glycoprotein，P-gp；也稱ATP binding cassette B1，ABCB1)、多藥耐藥相關蛋白-1(multidrug resistance-associated protein 1，MRP1；也稱ATP binding cassette C1，ABCC1)和乳腺癌耐藥蛋白(breast cancer resistance protein，BCRP，也稱ATP binding cassette G2，ABCG2)。伊馬替尼耐藥相關的攝入性轉(zhuǎn)運蛋白主要為人有機陽離子轉(zhuǎn)運體1(human organic cation transporter 1，hOCT-1)。

伊馬替尼耐藥相關的藥物轉(zhuǎn)運蛋白中研究較多的是P-gp。P-gp是由多藥耐藥基因MDR1編碼的一種跨膜糖蛋白，它消耗ATP的同時將胞內(nèi)親脂性的藥物泵出細胞，通過降低胞內(nèi)藥物濃度而導致耐藥的發(fā)生。Mahon等[25]首次報告，伊馬替尼的耐藥與P-gp的高表達有關。但是，Hatziieremia等[31]發(fā)現(xiàn)，P-gp介導的耐藥在CD34+的CML祖細胞中不明顯。Deenik等[32]發(fā)現(xiàn)，接受高劑量伊馬替尼治療的CML患者產(chǎn)生的耐藥與MDR1的基因多態(tài)性有關，表明伊馬替尼的耐藥與P-gp有關。

MRP1也是一類跨膜糖蛋白，它需通過消耗ATP與谷胱甘肽(glutathione，GSH)結合，將帶負電的藥物逆濃度梯度泵出細胞，降低細胞內(nèi)藥物濃度，從而導致耐藥。然而，也有學者持相反意見，如Mukai等[33]和White等[34]認為，伊馬替尼不是MRP1的底物，伊馬替尼耐藥與MRP1無關。

ABCG2首先從乳腺癌細胞中被發(fā)現(xiàn)，故又稱為BCRP。近年來研究發(fā)現(xiàn)，它在多藥耐藥方面起著不可忽視的作用。然而，對于伊馬替尼是ABCG2的底物還是抑制物，目前仍有爭議[35-36]。Nakanishi等[37]使表達BCR-ABL蛋白的CML細胞系K562細胞選擇性表達ABCG2，形成細胞系(K562/BCRP-MX10)，發(fā)現(xiàn)ABCG2可以保護BCR-ABL陽性的細胞免受伊馬替尼的殺傷；他們隨后發(fā)現(xiàn)，BCR-ABL蛋白通過激活PI3K-Akt通路上調(diào)ABCG2的表達，而伊馬替尼則通過抑制BCR-ABL蛋白的活性下調(diào)ABCG2的表達。但是， 該實驗是在人工導入ABCG2的基礎上進行的，而內(nèi)源性的ABCG2是否在CML細胞中具有以上作用仍待進一步研究。

hOCT-1是與伊馬替尼耐藥相關的攝入性轉(zhuǎn)運蛋白。Thomas等[38]認為，伊馬替尼通過hOCT1轉(zhuǎn)運到細胞內(nèi)。White等[34]也認為，hOCT1介導的伊馬替尼可進入細胞。Wang等[39]認為，hOCT1表達的減少可能和伊馬替尼的臨床效應不佳有關。

雖然已有大量藥物轉(zhuǎn)運蛋白的研究，但關于它們在伊馬替尼的耐藥機制中發(fā)揮的作用仍有爭議，仍需進行進一步的研究。

3.2.2 SIRT1去乙酰化增多 哺乳動物SIRT1是酵母沉默信息調(diào)節(jié)因子Sir2(silence information regulator 2)的同源物，是一種煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide，NAD)依賴的蛋白去乙?；竅40]。作為代謝應激感受因子，在細胞遭受代謝、氧化和毒性應激時，SIRT1通過將P53[41-42]，Ku70[43]和FOXO[44]蛋白等多種底物去乙?；S持細胞的存活。許多研究[45-48]表明，在原發(fā)性實體瘤和血液惡性腫瘤中，SIRT1的表達增多。然而，SIRT1激活在造血祖細胞的惡性轉(zhuǎn)化和CML發(fā)展中的作用仍不清楚。Wang等[49]發(fā)現(xiàn)，SIRT1在CML細胞株KCL-22和K562中表達明顯增加。隨后，Yuan等[50]證實，BCR-ABL可以在轉(zhuǎn)錄水平激活SIRT1。伊馬替尼可以通過抑制BCR-ABL而部分減少SIRT1的表達，進而增強CML細胞對伊馬替尼的敏感性。敲除SIRT1基因并聯(lián)合應用伊馬替尼可以延長CML小鼠模型的生存期。Wang等[51]證明，抑制SIRT1的去乙?；蚯贸齋IRT1基因可以阻斷應用酪氨酸激酶抑制劑導致的BCR-ABL獲得性突變以及CML復發(fā)。以上研究表明，SIRT1可能成為克服伊馬替尼耐藥的潛在治療靶點。

3.2.3 SK-1/S1P表達的增加 鞘磷脂(sphingomyelin)是膜脂質(zhì)的一個家族，包括神經(jīng)酰胺(ceramide，Cer)、鞘氨醇(sphingosine，Sph)和1-磷酸鞘氨醇(sphingosine 1-phosphate，S1P)等，對調(diào)節(jié)脂質(zhì)雙分子層的流動性和結構具有重要作用[52]。這些分子在細胞增殖、凋亡、轉(zhuǎn)移和衰老及炎性反應中發(fā)揮了必要作用[53-55]。Cer發(fā)揮促細胞凋亡的作用，而S1P則促進細胞增殖或抗凋亡。Cer可被神經(jīng)酰胺酶水解成鞘氨醇(Sph)，在鞘氨醇激酶(sphingosine kinase，SK)中的SK-1或SK-2的作用下，Sph被磷酸化，得到S1P[56]。Baran等[57]報告，在K562細胞株中，SK-1介導的Cer和S1P平衡的改變導致了伊馬替尼的耐藥，但機制尚不明確。Salas等[58]證明，SK-1/S1P通過抑制伊馬替尼耐藥細胞株中蛋白酶體對BCR-ABL的降解，加強BCR-ABL蛋白的穩(wěn)定性；相反，敲除SK-1則可明顯降低耐藥細胞株BCR-ABL的穩(wěn)定性。

3.2.4 Twist1基因表達增多 Twist1基因是堿性螺旋-環(huán)-螺旋轉(zhuǎn)錄因子的重要成員，它作為轉(zhuǎn)錄因子參與胚胎的形成、未分化細胞的增殖和細胞的存活[59-61]。許多研究表明，Twist1作為重要的癌基因，在表皮-間葉細胞轉(zhuǎn)換(epithelial-mesenchymal transition，EMT)過程中起重要作用，參與多種實體腫瘤的發(fā)生和發(fā)展過程，但其在造血系統(tǒng)疾病中的作用仍不明確。Cosset等[62]認為，Twist1基因可能參與CML的發(fā)生發(fā)展過程及伊馬替尼的耐藥。他們發(fā)現(xiàn)在CML活動期的患者中，Twist1基因是上調(diào)的；酪氨酸激酶抑制劑能下調(diào)Twist1基因的水平，而在酪氨酸激酶抑制劑耐藥的患者中，Twist1基因是上調(diào)的。有關Twist1基因在CML中的作用以及與酪氨酸激酶抑制劑耐藥關系，尚有待進一步研究。

綜上所述，伊馬替尼的出現(xiàn)為CML的治療及改善患者預后提供了希望，但隨著臨床應用的推廣，其耐藥現(xiàn)象不斷顯現(xiàn)。了解伊馬替尼耐藥的機制有助于制定合理的治療方案，從而進一步提高CML患者的生存率和生存質(zhì)量。伊馬替尼的耐藥機制非常復雜，不僅涉及BCR-ABL蛋白的突變及表達水平改變等BCR-ABL依賴的耐藥機制，還包括多種非BCR-ABL依賴的耐藥機制。雖然在伊馬替尼的耐藥機制研究方面已取得很大的進步，但仍未被完全闡明，且多種耐藥機制之間的相互作用亦不明確。靶向多種耐藥位點可能成為克服伊馬替尼耐藥的新方向。

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