-
摘要: PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。Abstract: The PI3K/Akt/mTOR signaling pathway is involved in inhibiting the apoptosis of tumor cells, promoting cell survival, and regulating cell cycle, as well as in the angiogenesis, invasion, and metastasis of tumors. Therefore, this pathway has an important function in tumorigenesis, tumor growth, prognosis, and treatment. So the PI3K/Akt/mTOR signaling pathway as a new therapeutic target and has been highlighted in breast cancer research. Pre-clinical studies have confirmed that mTOR inhibitors achieve anticancer effects by targeting the PI3K/Akt/mTOR signaling pathway. Endocrine therapy is the primary method in breast cancer treatment. However, this therapy has instances of drug resistance because chemotherapy and other treatments are administered to patients. Only blocking one site point does not meet the treatment needs because more signaling pathways have been identified. Identifying a common inhibitory site for multiple pathways has become the focus of research. The mTOR inhibitor is the crossing point of multiple signaling pathways and has attracted extensive attention in this subject.
-
Key words:
- breast cancer /
- drug resistance /
- mTOR inhibitor /
- endocrine therapy
-
[1] Chumsri S, Howes T, Bao T, et al. Aromatase, aromatase inhibitors, and breast cancer[J]. J Steroid Biochem Mol Biol, 2011, 125(1-2): 13-22. https://www.sciencedirect.com/science/article/pii/S0960076011000331 [2] Mouridsen H, Gershanovich M, Sun Y, et al. Phase Ⅲ study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women:analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group[J]. J Clin Oncol, 2003, 21(11):2101-2109. https://www.ncbi.nlm.nih.gov/pubmed/15284276 [3] Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk[J]. Endocr Relat Cancer, 2006, 13(Suppl 1):S15-24. https://www.ncbi.nlm.nih.gov/pubmed/17259554 [4] Bachelot T, Bourgier C, Cropet C, et al. Randomized phase Ⅱ trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study[J]. J Clin Oncol, 2012, 30(22):2718-2724. http://jnci.oxfordjournals.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=30/22/2718 [5] Jelovac D, Sabnis G, Long BJ, et al. Activation of mitogen-activated protein kinase in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole[J]. Cancer Res, 2005, 65 (12):5380-5389. http://www.biomedcentral.com/pubmed/15958587 [6] Miller TW, Hennessy BT, González-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. http://www.biomedcentral.com/pubmed/20530877 [7] Yue W, Fan P, Wang J, et al. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells[J]. J Steroid Biochem Mol Biol, 2007, 106(1-5):102-110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147683/ [8] Dobashi Y, Watanabe Y, Miwa C, et al. Mammalian target of rapamycin: a central node of complex signaling cascades[J]. Int J Clin Exp Pathol, 2011, 4(5):476-495. http://europepmc.org/abstract/MED/21738819 [9] Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism[J]. Cell, 2006, 124(3):471-484. http://europepmc.org/abstract/MED/16469695 [10] Alers S, Löffler AS, Wesselborg S, et al. Role of AMPK-mTOR-Ulk1/ 2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks[J]. Mol Cell Biol, 2012, 32(1):2-11. http://europepmc.org/articles/PMC3255710/ [11] deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity[J]. Clin Cancer Res, 2004, 10(23):8059-8067. http://www.ncbi.nlm.nih.gov/pubmed/15585641?dopt=Abstract [12] Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer[J]. Clin Cancer Res, 2005, 11(14):5319-5328. http://onlinelibrary.wiley.com/resolve/reference/PMED?id=16033851 [13] Beeram M, Tan QT, Tekmal RR, et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling[J]. Ann Oncol, 2007, 18(8):1323-1328. http://europepmc.org/abstract/med/17693645 [14] Alexander W. San antonio breast cancer symposium[J]. PT, 2011, 36 (3):156-158. https://www.ajmc.com/conference/sabcs [15] Bachelot T, Bourgier C, Cropet C, et al. Randomized phase Ⅱ trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study[J]. J Clin Oncol, 2012, 30(22):2718-2724. http://jnci.oxfordjournals.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=30/22/2718 [16] 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. http://europepmc.org/abstract/MED/24415983 [17] Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis[J]. Adv Ther, 2013, 30(10):870-884. doi: 10.1007/s12325-013-0060-1 [18] Gomez-Fernandez C, Garden BC, Wu S, et al. The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: a systematic review of the literature and meta-analysis[J]. Eur J Cancer, 2012, 48(3):340-346. http://www.sciencedirect.com/science/article/pii/S0959804911009683 [19] Porta C, Osanto S, Ravaud A, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma[J]. Eur J Cancer, 2011, 47(9):1287-1298. http://www.biomedcentral.com/pubmed/21481584 [20] Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies[J]. J Natl Cancer Inst, 2012, 104(2):93-113. http://europepmc.org/abstract/med/22235142 [21] Baselga J, Semiglazov V, van Dam P, et al. Phase Ⅱ randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer[J]. J Clin Oncol, 2009, 27(16):2630-2637. https://pubmed.ncbi.nlm.nih.gov/19380449/ [22] Sendur MA, Zengin N, Aksoy S, et al. Everolimus: a new hope for patients with breast cancer[J]. Curr Med Res Opin, 2014, 30(1):75-87. https://www.ncbi.nlm.nih.gov/pubmed/24050600 [23] Martina JA, Chen Y, Gucek M, et al. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB[J]. Autophagy, 2012, 8(6):903-914. https://pubmed.ncbi.nlm.nih.gov/22576015/
点击查看大图
计量
- 文章访问数: 28
- HTML全文浏览量: 40
- PDF下载量: 0
- 被引次数: 0