• 上海交通大學(xué)醫(yī)學(xué)院附屬第三人民醫(yī)院普外一科（上海 201999）;

目的 　總結(jié)雷帕霉素靶蛋白（mTOR）及其信號通路在胃癌化療耐藥中的研究現(xiàn)狀。
方法 　查閱國內(nèi)外近年來有關(guān)mTOR信號通路在胃癌化療耐藥中作用機理的文獻并做綜述。
結(jié)果 　mTOR作為mTOR信號轉(zhuǎn)導(dǎo)通路中一個重要的信號分子，參與了細(xì)胞的生長、增殖以及代謝，血管新生等重要過程。mTOR信號通路相關(guān)分子在胃癌中過表達(dá)，在胃癌的化療耐藥中起重要作用。此外，腫瘤干細(xì)胞也參與了胃癌的化療耐藥。
結(jié)論 　mTOR及其信號通路在胃癌的化療耐藥中起重要作用。以mTOR為靶點，聯(lián)合應(yīng)用mTOR抑制劑和化療藥物治療胃癌，對克服胃癌化療耐藥已初見成效，具有廣闊的臨床應(yīng)用前景。

引用本文： 朱優(yōu)龍,姜波健,俞繼衛(wèi). mTOR及其信號通路在胃癌化療耐藥中的研究進展△. 中國普外基礎(chǔ)與臨床雜志, 2012, 19(12): 1352-1356. doi: 復(fù)制

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2. Menges M， Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction[J].J Cancer Res Clin Oncol， 2009， 135(1)：29-38.
3. Al-Batran SE， Ducreux M， Ohtsu A. mTOR as a therapeutic target in patients with gastric cancer[J]. Int J Cancer， 2012， 130(3)：491-496.
4. Wander SA， Hennessy BT， Slingerland JM. Next-generation mTOR inhibitors in clinical oncology：how pathway complexity informs therapeutic strategy[J]. J Clin Invest， 2011， 121(4)：1231-1241.
5. Sarbassov DD， Ali SM， Sabatini DM. Growing roles for the mTOR pathway[J]. Curr Opin Cell Biol， 2005， 17(6)：596-603.
6. Yu G， Wang J， Chen Y， et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer[J]. Clin Cancer Res， 2009， 15(5)：1821-1829.
7. Kamata S， Kishimoto T， Kobayashi S， et al. Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancercells[J]. Cancer Biol Ther， 2007， 6(7)：1036-1043.
8. Lee KH， Hur HS， Im SA， et al. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregula-ting thymidylate synthase[J]. Cancer Lett， 2010， 299(1)：22-28.
9. Semenza GL. HIF-1：upstream and downstream of cancer metab-olism[J]. Curr Opin Genet Dev， 2010， 20(1)：51-56.
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12. Rohwer N， Dame C， Haugstetter A， et al. Hypoxia-inducible factor 1α determines gastric cancer chemosensitivity via modulation of p53 and NF-κB[J]. PLoS One， 2010， 5(8)：e12038.
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14. 姜海廣， 陸瑞祺， 吳巨鋼， 等. 基質(zhì)細(xì)胞源性因子-1α/CXC趨化因子受體-4軸經(jīng)PI3K/Akt通路對胃癌細(xì)胞CD133表達(dá)的調(diào)控作用[J]. 中華實驗外科雜志， 2012， 29(3)：378-380.
15. Anderson EC， Hessman C， Levin TG， et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response[J]. Cancer， 2011， 3(1)：319-339.
16. Dirks P. Cancer stem cells：invitation to a second round[J].Nature， 2010， 466(7302)：40-41.
17. Frank NY， Schatton T， Frank MH. The therapeutic promise of the cancer stem cell concept[J]. J Clin Invest， 2010， 120(1)：41-50.
18. Shafee N， Smith CR， Wei Shuanzeng， et al. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors[J]. Cancer Res， 2008， 68(9)：3243-3250.
19. To K， Fotovati A， Reipas KM， et al. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal， mammosphere growth， and drug resistance[J]. Cancer Res， 2010， 70(7)：2840-2851.
20. Cammareri P， Scopelliti A， Todaro M， et al. Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells[J]. Cancer Res， 2010， 70(11)：4655-4665.
21. Zhang L， Jiao M， Li L， et al. Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties[J]. J Cancer Res Clin Oncol， 2012， 138(4)：675-686.
22. Jimeno A， Rudek MA， Kulesza P， et al. Pharmacodynamic-guided modified continuous reassessment method-based， dose-finding study of rapamycin in adult patients with solid tumors[J]. J Clin Oncol， 2008， 26(25)：4172-4179.
23. Hashimoto I， Koizumi K， Tatematsu M， et al. Blocking on the CXCR4/mTOR signaling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells[J]. Eur J Cancer， 2008， 44(7)：1022-1029.
24. Cejka D， Preusser M， Fuereder T， et al. mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo[J]. Anticancer Res， 2008， 28(6A)：3801-3808.
25. Cejka D， Preusser M， Woehrer A， et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo[J]. Cancer Biol Ther， 2008， 7(9)：1377-1385.
26. Feldman ME， Apsel B， Uotila A， et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2[J]. PLoS Biol， 2009， 7(2)：e1000038.
27. Choo AY， Yoon SO， Kim SG， et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation[J]. Proc Natl Acad Sci U S A， 2008， 105(45)：17414-17419.
28. Thoreen CC， Kang SA， Chang JW， et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1[J]. J Biol Chem， 2009， 284(12)：8023-8032.
29. O’reilly KE， Rojo F， She QB， et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt[J]. Cancer Res， 2006， 66(3)：1500-1508.
30. Breuleux M， Klopfenstein M， Stephan C， et al. Increased Akt S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition[J]. Mol Cancer Ther， 2009， 8(4)：742-753.
31. García-Martínez JM， Moran J， Clarke RG， et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)[J]. Biochem J， 2009， 421(1)：29-42.
32. Chresta CM， Davies BR， Hickson I， et al. AZD8055 is a potent， selective， and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity[J]. Cancer Res， 2010， 70(1)：288-298.
33. Yu K， Shi C， Toral-Barza L， et al. Beyond rapalog therapy：preclinical pharmacology and antitumor activity of WYE-125132， an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res， 2010， 70(2)：621-631.
34. Bhagwat SV， Gokhale PC， Crew AP， et al. Preclinical characterization of OSI-027， a potent and selective inhibitor of mTORC1 and mTORC2：distinct from rapamycin[J]. Mol Cancer Ther， 2011， 10(8)：1394-1406.
35. Füreder T， Wanek T， Pflegerl P， et al. BEZ235 impairs gastriccancer growth by inhibition of PI3K/mTOR in vitro and in vivo[J]. BMC Pharmacol， 2010， 10(Suppl 1)：A41.
  1. 1. Lin Y， Ueda J， Kikuchi S， et al. Comparative epidemiology of gastric cancer between Japan and China[J]. World J Gastroenterol， 2011， 17(39)：4421-4428.
  2. 2. Menges M， Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction[J].J Cancer Res Clin Oncol， 2009， 135(1)：29-38.
  3. 3. Al-Batran SE， Ducreux M， Ohtsu A. mTOR as a therapeutic target in patients with gastric cancer[J]. Int J Cancer， 2012， 130(3)：491-496.
  4. 4. Wander SA， Hennessy BT， Slingerland JM. Next-generation mTOR inhibitors in clinical oncology：how pathway complexity informs therapeutic strategy[J]. J Clin Invest， 2011， 121(4)：1231-1241.
  5. 5. Sarbassov DD， Ali SM， Sabatini DM. Growing roles for the mTOR pathway[J]. Curr Opin Cell Biol， 2005， 17(6)：596-603.
  6. 6. Yu G， Wang J， Chen Y， et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer[J]. Clin Cancer Res， 2009， 15(5)：1821-1829.
  7. 7. Kamata S， Kishimoto T， Kobayashi S， et al. Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancercells[J]. Cancer Biol Ther， 2007， 6(7)：1036-1043.
  8. 8. Lee KH， Hur HS， Im SA， et al. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregula-ting thymidylate synthase[J]. Cancer Lett， 2010， 299(1)：22-28.
  9. 9. Semenza GL. HIF-1：upstream and downstream of cancer metab-olism[J]. Curr Opin Genet Dev， 2010， 20(1)：51-56.
  10. 10. Nakamura J， Kitajima Y， Kai K， et al. Hypoxia-inducible factor-1alpha expression predicts the response to 5-fluorouracil-basedadjuvant chemotherapy in advanced gastric cancer[J]. Oncol Rep， 2009， 22(4)：693-699.
  11. 11. Nakamura J， Kitajima Y， Kai K， et al. HIF-1alpha is an unfavor-able determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy[J]. Int J Cancer， 2010， 127(5)：1158-1171.
  12. 12. Rohwer N， Dame C， Haugstetter A， et al. Hypoxia-inducible factor 1α determines gastric cancer chemosensitivity via modulation of p53 and NF-κB[J]. PLoS One， 2010， 5(8)：e12038.
  13. 13. Kim HK， Choi IJ， Kim CG， et al. A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients[J]. PLoS One， 2011， 6(2)：e16694.
  14. 14. 姜海廣， 陸瑞祺， 吳巨鋼， 等. 基質(zhì)細(xì)胞源性因子-1α/CXC趨化因子受體-4軸經(jīng)PI3K/Akt通路對胃癌細(xì)胞CD133表達(dá)的調(diào)控作用[J]. 中華實驗外科雜志， 2012， 29(3)：378-380.
  15. 15. Anderson EC， Hessman C， Levin TG， et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response[J]. Cancer， 2011， 3(1)：319-339.
  16. 16. Dirks P. Cancer stem cells：invitation to a second round[J].Nature， 2010， 466(7302)：40-41.
  17. 17. Frank NY， Schatton T， Frank MH. The therapeutic promise of the cancer stem cell concept[J]. J Clin Invest， 2010， 120(1)：41-50.
  18. 18. Shafee N， Smith CR， Wei Shuanzeng， et al. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors[J]. Cancer Res， 2008， 68(9)：3243-3250.
  19. 19. To K， Fotovati A， Reipas KM， et al. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal， mammosphere growth， and drug resistance[J]. Cancer Res， 2010， 70(7)：2840-2851.
  20. 20. Cammareri P， Scopelliti A， Todaro M， et al. Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells[J]. Cancer Res， 2010， 70(11)：4655-4665.
  21. 21. Zhang L， Jiao M， Li L， et al. Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties[J]. J Cancer Res Clin Oncol， 2012， 138(4)：675-686.
  22. 22. Jimeno A， Rudek MA， Kulesza P， et al. Pharmacodynamic-guided modified continuous reassessment method-based， dose-finding study of rapamycin in adult patients with solid tumors[J]. J Clin Oncol， 2008， 26(25)：4172-4179.
  23. 23. Hashimoto I， Koizumi K， Tatematsu M， et al. Blocking on the CXCR4/mTOR signaling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells[J]. Eur J Cancer， 2008， 44(7)：1022-1029.
  24. 24. Cejka D， Preusser M， Fuereder T， et al. mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo[J]. Anticancer Res， 2008， 28(6A)：3801-3808.
  25. 25. Cejka D， Preusser M， Woehrer A， et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo[J]. Cancer Biol Ther， 2008， 7(9)：1377-1385.
  26. 26. Feldman ME， Apsel B， Uotila A， et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2[J]. PLoS Biol， 2009， 7(2)：e1000038.
  27. 27. Choo AY， Yoon SO， Kim SG， et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation[J]. Proc Natl Acad Sci U S A， 2008， 105(45)：17414-17419.
  28. 28. Thoreen CC， Kang SA， Chang JW， et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1[J]. J Biol Chem， 2009， 284(12)：8023-8032.
  29. 29. O’reilly KE， Rojo F， She QB， et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt[J]. Cancer Res， 2006， 66(3)：1500-1508.
  30. 30. Breuleux M， Klopfenstein M， Stephan C， et al. Increased Akt S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition[J]. Mol Cancer Ther， 2009， 8(4)：742-753.
  31. 31. García-Martínez JM， Moran J， Clarke RG， et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)[J]. Biochem J， 2009， 421(1)：29-42.
  32. 32. Chresta CM， Davies BR， Hickson I， et al. AZD8055 is a potent， selective， and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity[J]. Cancer Res， 2010， 70(1)：288-298.
  33. 33. Yu K， Shi C， Toral-Barza L， et al. Beyond rapalog therapy：preclinical pharmacology and antitumor activity of WYE-125132， an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res， 2010， 70(2)：621-631.
  34. 34. Bhagwat SV， Gokhale PC， Crew AP， et al. Preclinical characterization of OSI-027， a potent and selective inhibitor of mTORC1 and mTORC2：distinct from rapamycin[J]. Mol Cancer Ther， 2011， 10(8)：1394-1406.
  35. 35. Füreder T， Wanek T， Pflegerl P， et al. BEZ235 impairs gastriccancer growth by inhibition of PI3K/mTOR in vitro and in vivo[J]. BMC Pharmacol， 2010， 10(Suppl 1)：A41.