脂肪酸合成酶促进HER2阳性乳腺癌曲妥珠单抗耐药的研究进展

章杰 徐菁铭 王蓓

[摘要] 约25%～30%乳腺癌为HER2阳性乳腺癌，近年来，虽然抗HER2分子靶向药曲妥珠单抗显著改善HER2阳性乳腺癌的治疗策略和预后，但原发性或继发性曲妥珠单抗耐药越来越受到关注，临床耐药现象亦尚未完全阐明。脂肪酸合成酶（fatty acid synthase，FASN）是内源性脂肪酸从头合成途径的关键酶，FASN过表达与HER2阳性乳腺癌复发和预后密切相关，并在曲妥珠耐药中发挥重要作用，有望成为规避曲妥珠单抗耐药的新靶点，本文就该机制进展作一综述。

[关键词] HER2阳性乳腺癌;脂肪酸合成酶;曲妥珠单抗;耐药机制

[中图分类号] R735.2          [文献标识码] A          [文章编号] 1673-9701（2020）12-0179-05

[Abstract] About 25%-30% of breast cancers are HER2-positive breast cancers. In recent years， although the anti-HER2 molecule targeting drug trastuzumab has significantly improved the treatment strategy and prognosis of HER2-positive breast cancer， primary or secondary trastuzumab resistance has received increasing attention， and clinical resistance has not been fully elucidated. Fatty acid synthase（FASN） is a key enzyme in the de novo synthesis pathway of endogenous fatty acids. FASN overexpression is closely related to the recurrence and prognosis of HER2-positive breast cancer， and plays an important role in trastuzumab resistance. It is expected to become a new target for avoiding trastuzumab resistance. This article reviews the progress of the mechanism.

[Key words] HER2-positive breast cancer; Fatty acid synthase（FASN）; Trastuzumab; Drug resistance mechanism

据美国国家癌症中心2019年发布的数据显示，美国乳腺癌依然占女性恶性肿瘤的首位，约有380万女性有乳腺癌病史，新发268 600例，乳腺癌已严重影响女性健康[1]。乳腺癌分子分型中约25%～30%的乳腺癌为人表皮生长因子受体-2（Human epidermal growth factor receptor-2，HER2）阳性乳腺癌，该类型乳腺癌浸润强，预后差[2]。虽然HER2靶向药物曲妥珠单抗（Trastuzumab）联合化疗可延长辅助、新辅助及晚期HER2阳性乳腺癌患者的无进展生存期（Time to progress，TTP）和总生存期（Overall survival，OS），但临床研究表明70%的HER2阳性乳腺癌对曲妥珠单抗并无反应，联合化疗反应率也仅50%，即使最初曲妥珠单抗敏感的乳腺癌也大部分在1年内出现进展[3，4]。因此，有关曲妥珠单抗先天性或继发性耐药的机制一直是研究热点。目前已明确曲妥珠单抗耐药与下列因素有关：曲妥珠单抗新辅助治疗后肿瘤HER2阳性在体内转化为HER2阴性;肿瘤具有酶活性的p95HER2亚型突变;HER家族其他成员如HER1、HER3和HER4等过度表达或异常激活;PTEN丢失致PI3K/AKT/mTOR通路异常激活;功能性PI3KCA突变和AKT突变等[5，6]。为规避曲妥珠单抗耐药，临床优化曲妥珠单抗联合化疗方案、联合或序贯酪氨酸酶抑制剂、与帕妥珠单抗双靶治疗以及曲妥珠单抗-美坦辛偶联物（Ado-trastuzumab emtansine，T-DM1）等手段，虽然显著改善HER2阳性乳腺癌的治疗结局[6，7]，但临床耐药现象仍尚未完全阐明。因此，寻找新的规避曲妥珠单抗耐药手段是目前科研和临床共同关注的课题。内源性脂肪酸代谢是合成代谢和能量储存过程，在正常生理条件下不发挥主要调节作用，但对于肿瘤细胞是能量代谢和增殖的基础，脂肪酸合成酶（Fatty acid synthase，FASN）是内源性脂肪酸合成的關键酶。近年来，FASN在HER2阳性乳腺癌曲妥珠单抗耐药过程中发挥的作用越来越受到重视，有望成为规避曲妥珠单抗耐药的肿瘤代谢新靶点[8]，本文就该机制研究现状予以综述。

1 FASN调控脂质代谢促进肿瘤增殖概述

1.1 FASN概述

肿瘤细胞代谢重编程是肿瘤的标志之一，肿瘤脂质代谢与肿瘤调控网络间相互作用可促进肿瘤发生发展，致癌性生长信号通过调节脂质、葡萄糖和谷氨酰胺等代谢以适应肿瘤细胞的快速增殖[9]。内源性脂肪酸合成是肿瘤细胞脂质代谢促进肿瘤增殖的核心过程，而FASN是内源性脂肪酸乙酰辅酶A从头合成的关键酶。FASN为同源二聚体多功能酶蛋白，分子质量540 kDa，是由β-羟脂酰脱水酶、β-酮脂酰还原酶、β-酮脂酰合成酶、乙酰基转移酶和丙二酰基转移酶等七种酶聚合形成的多酶复合体，以乙酰辅酶A为引物，丙二酰单酰辅酶A为二碳的载体，依赖NADPH为还原剂，催化长链脂肪酸的从头合成，是调控棕榈酸酯合成的终止步骤[10]。正常细胞一般优先利用膳食脂肪酸，脂肪酸内源性合成极少，而肿瘤细胞对脂肪酸需求大，FASN基因常高表达，并且与肿瘤进展、耐药及预后不良有关[11]。因此，FASN有望作为肿瘤代谢新靶点。

[5] Brand？觔o M，Pondé NF，Poggio F，et al.Combination therapies for the treatment of HER2-positive breast cancer：Current and future prospects[J]. Expert Rev Anticancer Ther，2018，18（7）：629-649.

[6] Jiang N，Lin JJ，Wang J，et al.Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs[J]. Exp Ther Med， 2018，16（3）：2183-2192.

[7] Xu Z，Guo D，Jiang Z，et al.Novel HER2-targeting antibody-drug conjugates of trastuzumab beyond T-DM1 in breast cancer：Trastuzumab deruxtecan（DS-8201a） and （Vic-）trastuzumab duocarmazine（SYD985）[J]. Eur J Med Chem，2019，183：111682.

[8] Menendez JA，Lupu R.Fatty acid synthase（FASN） as a therapeutic target in breast cancer[J]. Expert Opin Ther Targets，2017，21（11）：1001-1016.

[9] Cheng C，Geng F，Cheng X，et al. Lipid metabolism reprogramming and its potential targets in cancer[J].Cancer Commun （Lond），2018，38（1）：27.

[10] Zhang JS，Lei JP，Wei GQ，et al.Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers： A review[J]. Pharm Biol，2016，54（9）：1919-1925.

[11] Angeles TS，Hudkins RL.Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors[J].Expert Opin Drug Discov，2016，11（12）：1187-1199.

[12] Koundouros N，Poulogiannis G.Reprogramming of fatty acid metabolism in cancer[J]. Br J Cancer，2020，122（1）：4-22.

[13] Ventura R，Mordec K，Waszczuk J，et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes，inhibiting signaling pathways，and reprogramming gene expression[J]. E Bio Medicine，2015，2（8）：808-824.

[14] Cui J，Diao J，Sun T，et al.13C Metabolic flux analysis of enhanced lipid accumulation modulated by ethanolamine in crypthecodinium cohnii[J]. Front Microbiol，2018，9：956.

[15] Guo D，Bell EH，Mischel P，et al.Targeting SREBP-1-driven lipid metabolism to treat cancer[J]. Curr Pharm Des，2014，20（15）：2619-2626.

[16] Zhu W，Lv C，Wang J，et al. Patuletin induces apoptosis of human breast cancer SK-BR-3 cell line via inhibiting fatty acid synthase gene expression and activity[J]. Oncol Lett，2017，14（6）：7449-7454.

[17] Monaco ME. Fatty acid metabolism in breast cancer subtypes[J].Oncotarget，2017，8（17）：29487-29500.

[18] Corominas-Faja B，Vellon L，Cuyàs E，et al. Clinical and therapeutic relevance of the metabolic oncogene fatty acid synthase in HER2+breast cancer[J].Histol Histopathol，2017，32（7）：687-698.

[19] Dumortier M，Ladam F，Damour I，et al. ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis[J].Breast Cancer Res，2018， 20（1）：73.

[20] Alwarawrah Y，Hughes P，Loiselle D，et al.Fasnall，a selective FASN inhibitor，shows potent anti-tumor activity in the MMTV-Neu Model of HER2（+） breast cancer[J]. Cell Chem Biol，2016，23（6）：678-688.

[21] Puig T，Aguilar H，Cufí S，et al. A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines[J]. Breast Cancer Res，2011，13（6）：R131.

[22] Jones SF，Infante JR. Molecular pathways：Fatty acid synthase[J]. Clin Cancer Res，2015，21（24）：5434-5438.

[23] Furukawa K，Ohmi Y，Ohkawa Y，et al.New era of research on cancer-associated glycosphingolipids[J]. Cancer Sci，2019，110（5）：1544-1551.

[24] Menendez JA.Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth：Molecular mechanisms and therapeutic perspectives[J]. Biochim Biophys Acta，2010，1801（3）：381-391.

[25] Blancafort A，Giró-Perafita A，Oliveras G，et al.Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs[J]. PLoS One，2015，10（6）：e0131241.

[26] Zhao M，Zhang Z.Glucose transporter regulation in cancer：A profile and the loops[J]. Crit Rev Eukaryot Gene Expr，2016，26（3）：223-238.

[27] Bollu LR，Katreddy RR，Blessing AM，et al.Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation[J].Oncotarget，2015，6（33）：34992-35003.

[28] Wu X，Dong Z，Wang CJ，et al. FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1[J].Proc Natl Acad Sci USA，2016，113（45）：E6965-E6973.

[29] Kinlaw WB，Baures PW，Lupien LE，et al. Fatty acids and breast cancer： Make them on site or have them delivered[J]. J Cell Physiol，2016，231（10）：2128-2141.

[30] Deshmukh SK，Singh AP，Singh S.ETV4：An emerging target in pancreatic cancer[J]. Oncoscience，2018，5（9-10）：260-261.

[31] Kherrouche Z，Monte D，Werkmeister E，et al.PEA3 transcription factors are downstream effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor cells[J]. Mol Oncol，2015，9（9）：1852-1867.

[32] Schcolnik-Cabrera A，Chávez-Blanco A，Domínguez-Gómez G，et al. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy[J]. Expert Opin Investig Drugs，2018，27（5）：475-489.

[33] Menendez JA，Lupu R.Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells[J]. Oncogenesis，2017，6（2）：e299.

（收稿日期：2020-02-10）