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信號通路介導(dǎo)乳腺癌內(nèi)分泌治療耐藥的研究進(jìn)展

2018-12-12 10:46范鳳鳳郭宇
中國醫(yī)學(xué)創(chuàng)新 2018年24期
關(guān)鍵詞:靶向治療耐藥乳腺癌

范鳳鳳 郭宇

【摘要】 乳腺癌內(nèi)分泌治療作為乳腺癌綜合治療的方法之一,具有不可替代的重要性。然而,原發(fā)性和繼發(fā)性耐藥仍是內(nèi)分泌治療中面臨的難題。文章旨在對介導(dǎo)乳腺癌內(nèi)分泌耐藥的信號通路及臨床試驗(yàn)中靶向治療的進(jìn)展進(jìn)行綜述,為臨床內(nèi)分泌治療提供新的方向。

【關(guān)鍵詞】 乳腺癌; 內(nèi)分泌治療; 耐藥; 靶向治療

【Abstract】 Endocrine therapy for breast cancer as one of the methods of comprehensive treatment of breast cancer has irreplaceable importance.However,primary and secondary drug resistance is still a difficult problem in endocrine therapy.The purpose of this article is to review the signal pathway of mediating endocrine resistance in breast cancer and the progress of targeted therapy in clinical trials in order to provide a new direction for clinical endocrine therapy.

【Key words】 Breast cancer; Endocrine therapy; Drug resistance; Targeted therapy

First-authors address:Medical School of Ningbo University,Ningbo 315000,China

doi:10.3969/j.issn.1674-4985.2018.24.040

乳腺癌是全球范圍內(nèi)女性發(fā)病率最高的惡性腫瘤,持續(xù)升高的發(fā)病率和死亡率,嚴(yán)重危害了女性的生命和健康。據(jù)統(tǒng)計(jì),有60%~75%的浸潤性乳腺癌患者分子分型為激素受體陽性,故內(nèi)分泌治療(endocrine therapy,ET)對這類患者而言是十分重要的治療方式[1]。內(nèi)分泌治療,與化療相比毒性低,且較易耐受,成效顯著,明顯降低了激素受體陽性乳腺癌患者的復(fù)發(fā)率[2-3]。但是,并非所有的激素受體陽性患者對內(nèi)分泌治療敏感,一部分患者可表現(xiàn)為原發(fā)或繼發(fā)性耐藥,從而導(dǎo)致腫瘤進(jìn)展或復(fù)發(fā)。研究表明,多種生長因子信號通路的激活、雌激素受體的表達(dá)及功能異常、腫瘤微環(huán)境的改變等異常均能導(dǎo)致乳腺癌內(nèi)分泌治療耐藥[4-5]。本文綜述了介導(dǎo)乳腺癌內(nèi)分泌耐藥的信號通路及臨床試驗(yàn)中靶向治療的效果,以期為ER陽性乳腺癌治療提供新對策。

1 信號通路

1.1 PI3K/Akt/mTOR信號通路 PI3K/Akt/mTOR信號通路是細(xì)胞內(nèi)的重要信號通路,在調(diào)節(jié)腫瘤細(xì)胞的增殖、分化、轉(zhuǎn)移過程中發(fā)揮重要作用,該信號通路的激活與乳腺癌的發(fā)生和發(fā)展有密切關(guān)系[6]。PI3Ks家族蛋白可分為Ⅰ、Ⅱ、Ⅲ類。PI3K被激活后的產(chǎn)物與Akt的PH區(qū)結(jié)合,激活A(yù)kt后進(jìn)一步激活下游的因子,下游mTOR的活性因而增強(qiáng),使ER磷酸化,形成耐藥細(xì)胞。mTOR是一類絲氨酸/蘇氨酸蛋白激酶,是PI3K/Akt信號通路下游的重要效應(yīng)分子,mTOR可接受上游來自Her-2、IGFR、EGFR等生長因子受體的信號,引起PI3K/Akt/mTOR信號通路激活,mTOR的表達(dá)上調(diào),調(diào)控了腫瘤細(xì)胞的增殖、分化和轉(zhuǎn)移,導(dǎo)致繼發(fā)性內(nèi)分泌耐藥[7]。PI3K/Akt/mTOR信號通路的激活除上游信號傳遞外,PI3K突變和PTEN丟失也是重要原因。聯(lián)合分析9項(xiàng)研究表明,在激素受體陽性/HER-2陰性的乳腺癌中,PI3CA突變率最高,達(dá)到37%。有研究表明,內(nèi)源性Akt在他莫昔芬治療失敗的乳腺癌細(xì)胞MCF-7中表達(dá)增強(qiáng),引起乳腺癌細(xì)胞ER表達(dá)缺失,導(dǎo)致內(nèi)分泌治療耐藥;反之,抑制PI3K或Akt的活性可增強(qiáng)ER表達(dá),使細(xì)胞對內(nèi)分泌治療藥物的敏感性恢復(fù)[8]。

1.2 HER-2信號通路 研究表明,HER-2信號通路與ER通路之間存在交互通話的現(xiàn)象,HER-2過表達(dá)者往往伴隨ER陰性,而ER陽性組的HER-2陽性率顯著低于ER陰性者,HER-2陽性的患者內(nèi)分泌治療反應(yīng)低下。激素受體陽性和HER-2過表達(dá)患者的其中一條信號通路受抑制,會(huì)激活另一條通路,同時(shí)抑制ER和HER-2兩條通路更有效[9]。HER-2通路的激活,引起下游ERK1/2MAPK超活化,可干預(yù)ER與其共調(diào)節(jié)因子結(jié)合,降低ER表達(dá)水平,甚至誘導(dǎo)ER表達(dá)缺失[10]。Osborne等[11]的體外實(shí)驗(yàn)也證實(shí)了ER同HER-2信號轉(zhuǎn)導(dǎo)途徑的交互作用與內(nèi)分泌治療耐藥有關(guān)。生長因子激活HER-2信號通路后,同時(shí)激活特異性的蛋白激酶,使位于或靠近細(xì)胞膜的ER與生長因子的激酶受體結(jié)合并活化,活化的ER移至細(xì)胞核內(nèi)與DNA結(jié)合,通過轉(zhuǎn)錄和翻譯,產(chǎn)生相應(yīng)的功能蛋白,使腫瘤細(xì)胞增殖,內(nèi)分泌治療失敗。

1.3 絲裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信號通路 MAPK激酶是細(xì)胞增生和凋亡信號轉(zhuǎn)導(dǎo)的關(guān)鍵蛋白激酶,在不同的信號轉(zhuǎn)導(dǎo)途徑中均有表達(dá)。MAPK信號通路是細(xì)胞生物信號傳導(dǎo)通路中的重要一員,促進(jìn)細(xì)胞的分裂、增殖和分化,與腫瘤進(jìn)展和藥物耐藥密切相關(guān)[12]。MAPK主要包括ERK1/2、JNK、P38、和ERK5四條通路,其中ERK1/2通路是MAPK信號轉(zhuǎn)導(dǎo)系統(tǒng)的經(jīng)典通路。其信號通路由RAF絲氨酸/蘇氨酸激酶啟動(dòng),激活MAPK信號通路后,誘導(dǎo)ER的AF-1區(qū)的主要位點(diǎn),如Ser118、Ser167磷酸化,從而使對ER敏感的基因表達(dá)上調(diào),誘導(dǎo)內(nèi)分泌治療耐藥細(xì)胞的生長和增殖。Brodie等[13]利用來曲唑耐藥乳腺癌細(xì)胞LTLTCa,得出來曲唑耐藥細(xì)胞ER磷酸化水平明顯高于來曲唑敏感細(xì)胞的結(jié)論,細(xì)胞系中p-Raf、HER-2、p-MAPK及p-MEK1/2表達(dá)上調(diào),證實(shí)了ER與HER-2信號通路相互影響,使MAPK信號通路激活,從而誘導(dǎo)ER磷酸化,促進(jìn)乳腺癌細(xì)胞增殖。

2 靶向藥物在逆轉(zhuǎn)乳腺癌內(nèi)分泌治療耐藥中的研究進(jìn)展

2.1 mTOR抑制劑 mTOR抑制劑依維莫司與mTOR1結(jié)合阻斷mTOR,相關(guān)臨床研究表明其與內(nèi)分泌聯(lián)合治療在晚期內(nèi)分泌耐藥乳腺癌中顯示出明顯的獲益[14]。TAMRAD Ⅱ期臨床試驗(yàn)?zāi)康氖潜容^他莫昔芬單藥與他莫昔芬聯(lián)合依維莫司療效的差異[15],該研究入組111例既往芳香化酶抑制劑(AIs)輔助治療失敗的激素受體陽性/HER-2陰性的絕經(jīng)后轉(zhuǎn)移性乳腺癌患者,結(jié)果表明,治療6個(gè)月后,他莫昔芬聯(lián)合依維莫司組的臨床獲益率為61%,明顯高于他莫昔芬單藥組的42%(P=0.045);聯(lián)合組的疾病進(jìn)展時(shí)間為8.6個(gè)月同樣優(yōu)于單藥組的4.5個(gè)月(P=0.002),亞組分析示原發(fā)性芳香化酶抑制劑耐藥組的疾病進(jìn)展時(shí)間兩組之間比較,差異無統(tǒng)計(jì)學(xué)意義(5.4個(gè)月 vs 3.8個(gè)月,P>0.05),然而對于繼發(fā)耐藥組的患者,他莫昔芬聯(lián)合依維莫司組和單藥治療組的疾病進(jìn)展時(shí)間為分別為14.8個(gè)月vs 5.5個(gè)月(P=0.008 7),臨床獲益率顯著增高。BOLERO-2是依維莫司獲批乳腺癌適應(yīng)證的關(guān)鍵性Ⅲ期臨床試驗(yàn)[16],試驗(yàn)再次驗(yàn)證了依維莫司聯(lián)合內(nèi)分泌治療在既往內(nèi)分泌治療失敗的激素受體陽性晚期乳腺癌患者中的有效性。該研究納入724例激素受體陽性HER-2陰性晚期乳腺癌患者,特征為經(jīng)芳香化酶抑制劑(來曲唑或阿那曲唑)治療后出現(xiàn)進(jìn)展復(fù)發(fā),研究結(jié)果發(fā)現(xiàn),依維莫司聯(lián)合依西美坦組與依西美坦加安慰劑組相比中位無進(jìn)展生存期(PFS)明顯延長[11個(gè)月vs 4.1個(gè)月,HR=0.38,95%CI(0.31,0.48),P<0.001],總緩解率和臨床獲益率(兩者分別為12.6% vs 1.7%,51.3% vs 26.4%)也占顯著優(yōu)勢。

2.2 PI3K抑制劑 文獻(xiàn)[17]研究表明,PI3K抑制劑能阻止內(nèi)分泌治療耐藥的發(fā)生。Buparlisib(BKM120)是一種口服的泛Pan-PI3K抑制劑,BELLE-2為隨機(jī)雙盲安慰劑對照 Ⅲ期研究,研究納入1 147例絕經(jīng)后激素陽性/HER-2陰性局部晚期或轉(zhuǎn)移性乳腺癌患者,均為芳香化酶抑制劑治療中或治療后≤1年內(nèi)出現(xiàn)復(fù)發(fā)或轉(zhuǎn)移,根據(jù)PI3K通路的狀態(tài)和是否有內(nèi)臟轉(zhuǎn)移進(jìn)行分層,受試者被隨機(jī)分配到Buparlisib(100 mg/d)聯(lián)合氟維司群(500 mg)組和安慰劑聯(lián)合氟維司群(500 mg)組。Buparlisib聯(lián)合氟維司群組和氟維司群聯(lián)合安慰組的中位PFS分別為6.9個(gè)月和5.0個(gè)月(HR=0.78,P<0.001),顯示了一定的PFS獲益[18-19]。但由于該藥能通過血腦屏障的特性,造成了一系列不良反應(yīng),如焦慮、抑郁等[20-22],故目前尚未批準(zhǔn)用于臨床。

2.3 HER-2抑制劑 HER-2過表達(dá)在內(nèi)分泌原發(fā)耐藥中占重要地位,激素受體陽性HER-2陽性的乳腺癌患者中,內(nèi)分泌聯(lián)合HER-2抑制劑同樣為提高內(nèi)分泌治療的有效方法之一。隨機(jī)3期TAnDEM研究目的是比較曲妥珠單抗聯(lián)合阿那曲唑與阿那曲唑加安慰劑兩組的療效[23],EGF30008研究比較了拉帕替尼抗HER-2治療聯(lián)合來曲唑與來曲唑加安慰劑兩組的療效[24],兩個(gè)試驗(yàn)均是雙重阻斷ER和HER-2通路,與單阻斷ER通路相比,PFS有明顯改善,但是OS的改善不明顯。這兩項(xiàng)臨床試驗(yàn)一致的結(jié)果是對于絕經(jīng)后激素受體陽性HER-2陽性的復(fù)發(fā)轉(zhuǎn)移患者,AI單藥效果欠佳,對于既往內(nèi)分泌治療失敗的激素受體陽性HER-2陽性的乳腺癌患者,為了逆轉(zhuǎn)內(nèi)分泌治療耐藥,在內(nèi)分泌治療基礎(chǔ)上進(jìn)行抗HER-2治療是非常必要的。

2.4 CDK4/6抑制劑 細(xì)胞周期蛋白依賴性激酶(CDK)對細(xì)胞周期調(diào)控有重要作用,研究表明,抑制CDK4/6的活性,乳腺癌細(xì)胞增殖同樣受抑制[25],與內(nèi)分泌治療聯(lián)合可逆轉(zhuǎn)內(nèi)分泌耐藥。帕布昔利布(Palbociclib)是一種CDK4/6抑制劑,通過阻斷細(xì)胞周期從G1向S1期過渡,從而阻斷腫瘤細(xì)胞增殖[26]。隨著PALOMA-1、PALOMA-3和PALOMA-2臨床試驗(yàn)結(jié)果的先后公布,明確了Palbociclib能延緩或逆轉(zhuǎn)內(nèi)分泌耐藥,確立了聯(lián)合內(nèi)分泌雙重治療在HR/HER-2陰性晚期乳腺癌的重要地位[27-28]。

2.5 恩替諾特(entinostst) 組蛋白去乙酰酶復(fù)合體(HDAC)是雌激素轉(zhuǎn)錄復(fù)合物的關(guān)鍵組成部分,臨床前研究提示,HDAC抑制劑通過上調(diào)ER?表達(dá)或調(diào)節(jié)生長信號通路逆轉(zhuǎn)人ER?陽性乳腺癌細(xì)胞株,可逆轉(zhuǎn)激素受體陽性乳腺癌他莫昔芬/AI耐藥[29]?,F(xiàn)已確認(rèn)某些特異性HDACs在乳腺腫瘤中異常表達(dá)[30]。ENCORE 301 Ⅱ期臨床試驗(yàn)納入130例絕經(jīng)后非甾體AIs耐藥的晚期激素受體陽性乳腺癌患者,隨機(jī)分為依西美坦聯(lián)合恩替諾特組和依西美坦聯(lián)合安慰劑組,主要終點(diǎn)PFS分別為4.3個(gè)月和2.3個(gè)月(P=0.05),OS分別為28.1個(gè)月和19.8個(gè)月(P=0.036)[31]。基于上述結(jié)果,恩替諾特被美國FDA授予突破性療法認(rèn)定的新藥[32],作為FDA加速新藥研發(fā)上市的重要途徑。

2.6 EGFR抑制劑 研究表明,當(dāng)細(xì)胞內(nèi)EGFR表達(dá)水平明顯增高時(shí),細(xì)胞膜上的ER能夠激活EGFR/HER-2信號通路,從而導(dǎo)致內(nèi)分泌耐藥。吉非替尼是選擇性EGFR的受體酪氨酸激酶抑制劑,通過阻斷EGFR與ER的相互作用途徑,抑制MAPK信號轉(zhuǎn)導(dǎo),達(dá)到逆轉(zhuǎn)他莫昔芬耐藥的目的[33]。NCT00077025 Ⅱ期臨床試驗(yàn)中,入組了93例他莫昔芬治療后耐藥的絕經(jīng)后晚期乳腺癌患者,隨機(jī)分為兩組(阿那曲唑聯(lián)合吉非替尼組和阿那曲唑聯(lián)合安慰劑組),結(jié)果顯示,與阿那曲唑聯(lián)合安慰劑組相比,聯(lián)合吉非替尼組的臨床獲益率明顯增高,無病進(jìn)展時(shí)間顯著延長,分別為14.6個(gè)月比8.2個(gè)月(HR=0.55),但是尚未有明確的大樣本臨床獲益證據(jù),仍需前瞻性多中心研究進(jìn)一步求證[34]。

內(nèi)分泌治療耐藥是乳腺癌治療中一個(gè)尚未攻克的難題,如何逆轉(zhuǎn)或延緩內(nèi)分泌治療耐藥是目前乳腺癌治療研究的重點(diǎn)之一。期待在不久的將來,找到新的治療機(jī)制以及靶向藥物的多藥聯(lián)合治療方案,能顯著著提高乳腺癌內(nèi)分泌治療耐藥患者的療效。

參考文獻(xiàn)

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