mTOR抑制剂在乳腺癌内分泌及HER-2靶向治疗耐药中的研究进展

doi:10.3760/cma.j.issn.1673422X.2015.05.016

摘要/Abstract

摘要： 哺乳动物雷帕霉素靶蛋白（mTOR）位于磷脂酰肌醇3激酶（PI3K）蛋白激酶B（Akt）细胞信号通路的下游，已有研究表明该通路的异常激活与乳腺癌的内分泌及抗人表皮生长因子受体2（HER2）的靶向治疗耐药相关。在既往传统药物的基础上通过联合mTOR抑制剂阻断该条通路的异常活化，在防止肿瘤细胞的耐药性发展及恢复初始敏感性方面均体现出了良好的应用前景，mTOR抑制剂将有望成为乳腺癌治疗的新希望。

Abstract: Mammalian target of rapamycin (mTOR) locates at the downstream of phosphatidylinositol 3 kinase (PI3K)protein kinase B (Akt) cell signal transduction pathway. Studies find that the abnormal activation of this pathway is correlated with the endocrine and drug resistance of anti human epidermal growth factor receptor2 (HER2) target therapy in breast cancer. The combination with mTOR inhibitors based on the past traditional drugs can block the pathway and reflect a favourable application prospect in preventing the development of resistance and restoring the initial sensitivity on tumor cells. mTOR inhibitors are expected to be the new hope for the treatment of breast cancer.

段海明, 郑艳妮, 王闽全. mTOR抑制剂在乳腺癌内分泌及HER-2靶向治疗耐药中的研究进展[J]. 国际肿瘤学杂志, 2015, 42(5): 377-380.

DUAN Hai-Ming, ZHENG Yan-Ni, WANG Min-Quan. Progress of research on mTOR inhibitor in endocrine and HER2 targeted therapy resistance in breast cancer[J]. Journal of International Oncology, 2015, 42(5): 377-380.

参考文献

［1］宗喻, 沈坤炜. 内分泌治疗联合mTOR抑制剂靶向治疗激素受体阳性乳腺癌［J］. 中华医学杂志, 2012, 92(10):655656. ［2］ Martin LA, Andre F, Campone M, et al. mTOR inhibitors in advanced breast cancer:ready for prime time?［J］. Cancer Treat Rev, 2013, 39(7):742752. ［3］ Cui J, Germer K, Wu T, et al. Crosstalk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cell［J］. Cancer Res, 2012, 72(21):56255634. ［4］ Mayer I. Role of mTOR inhibition in preventing resistance and restoring sensitivity to hormonetargeted and HER2targeted therapies in breast cancer［J］. Clin Adv Hematol Oncol， 2013, 11(4):217224. ［5］ Inglis DJ, Lavranos TC, Beaumont DM, et al. The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitor in renal and breast cancer［J］. Cancer Biol Ther, 2014, 15(11):15521560. ［6］ McAuliffe PF, MericBernstam F, Mills GB, et al. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis［J］. Clin Breast Cancer， 2010， 10suppl3:S59S65. ［7］ Pignochino Y, Dell`Aglio C, Basirico M, et al. The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma perclinical models［J］. Clin Cancer Res, 2013, 19(8):21172131. ［8］ De Amicis F, Guido C, Santoro M, et al. A novel functional interplay between Progesterone ReceptorB and PTEN,via AKT,modulates autophagy in breast cancer cell［J］. J Cell Mol Med, 2014, 18(11):22522265. ［9］ Sabine VS, Crozier C, Brookes CL, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study［J］. J Clin Oncol, 2014, 32(27):29512958. ［10］ Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptorpositive Breast cancer［J］. Cancer Treat Rev, 2014, 40(7):862871. ［11］ Troxell ML, Levine J, Beadling C, et al. High Prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast［J］. Mod Pathol, 2010, 23(1):2737. ［12］ Loi S, HaibeKains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptorpositive breast cancer［J］. Proc Natl Acad Sci, 2010, 107(22):1020810213. ［13］ Li H, Zhu R, Wang L, et al. PIK3CA mutations mostly begin to develop in ductal carcinoma of the breast［J］. Exp Mol Pathol, 2010, 88(1):150155. ［14］ Berglund FM, Weerasinghe NR, Davidson L, et al. Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1［J］. Oncogene, 2013, 32(37):44174426. ［15］ Paplomata E, O`Regan R. The PI3K/AKT/mTOR pathway in breast cancer:targets,trials and biomarkers［J］. Ther Adv Med Oncol, 2014, 6(4):154166. ［16］ Roberts PJ, Usary JE, Darr DB, et al. Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models［J］. Clin Cancer Res, 2012, 18(19):52905303. ［17］ BrunnerKubath C, Shabbir W, Saferding V, et al. The PI3 kinase/mTOR blocker NVPBEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells［J］. Breast Cancer Res Treat, 2011, 129(2):387400. ［18］ Chalasani P, Stopeck A, Clarke K, et al. A pilot study of estradiol followed by exemestane for reversing endocrine resistance in postmenopausal women with hormone receptorpositive metastatic breast cancer［J］. Oncologist, 2014, 19(11):11271128. ［19］ Saxena R, Dwivedi A. ErbB family receptor inhibitors as therapeutic agents in breast cancer:current status and future clinical perspective［J］. Med Res Rev, 2012, 32(1):166215. ［20］ Flaherty KT, Puzanov I. Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma［J］. Biochem Pharmacol, 2010, 8(5),638646. ［21］ Miller TW, Hennessy BT, GonzalezAngulo AM, et al. Hyperactivation of phosphatidylinositol3 kinase promotes escape from hormone dependence in estrogen receptorpositive human breast cancer［J］. J Clin Invest, 2010, 120(7):24062413. ［22］ Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptorpositive advanced breast cancer［J］. N Engl J Med, 2012, 366(6):520529. ［23］ Palmieri C, Patten DK, Januszewski A, et al. Breast cancer:current and future endocrine therapies［J］. Mol Cell Endocrinol, 2014, 382(1):695723. ［24］ Chen X, Zhao M, Hao M, et al. Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer［J］. Mol Cancer Res, 2013, 11(10):12691278. ［25］ Vinayak S, Carlson RW. mTOR inhibitors in the treatment of breast cancer［J］. Oncology, 2013, 27(1):3844. ［26］ Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptorpositive, HER2negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study［J］. J Clin Oncol, 2012, 30(22):27182724. ［27］ Dhillon S. Everolimus in combination with exemestane:a review of its use in the treatment of patients with postmenopausal hormonereceptorpositive,HER2 negative advanced breasst cancer［J］. Drugs, 2013, 73(5):475485. ［28］ Qiao L, Liang Y, Mira RR, et al. Mammalian target of rapamycin(mTOR) inhibitiors and combined chemotherapy in breast cancer:a mataanalysis of randomized controlled trials［J］. Int J Clin Exp Med， 2014, 7(10):33333343. ［29］ Wolff AC, Lazar AA, Bondarenko I, et al. Randomized phase III placebocontrolled trial of letrozole plus oral temsirolimus as firstline endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer［J］. J Clin Oncol, 2013, 31(2):195202. ［30］ Campone M, Bachelot T, Gnant M, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer:subgroup analysis from the BOLERO2 study［J］. Eur J Cancer, 2013, 49(12):26212632. ［31］ Wang Y, Liu Y, Du Y, et al. The predictive role of phosphatase and tensin homolog(PTEN)loss,phosphoinositol3(PI3) Kinase(PIK3CA)mutation,and PI3K pathway activation in sensitivity to trastuzumab in HER2 positive breast cancer:a mataanalysis［J］. Curr Med Res Opin, 2013, 29(6):633642. ［32］ Miller TW, Forbes JT, Shah C, et al. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2overexpressing cancer cells［J］. Clin Cancer Res, 2009, 15(23):72667276. ［33］ Hurvitz SA, Dalenc F, Campone M, et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2 overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy［J］. Breast Cancer Res Treat, 2013, 141(3):437446. ［34］ Morrow PK, Wulf GM, Ensor J, et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001)in patients with HER2 overexpressing metastatic breast cancer who progressed on trastuzumabbased therapy［J］. J Clin Oncol, 2011, 29(23):31263132. ［35］ Jerusalem G, Fasolo A, Cardoso F, et al. Phrase Ⅰ of trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pretreated patients with HER2overexpressing metastatic breast cancer［J］. Breast Cancer Res Treat, 2011, 125(2):447455.