P13K/AKT/MTOR信号通路抑制剂在胃癌中的研究进展
摘要
胃癌是最常见的恶性肿瘤之一,随着人们对胃癌生物学行为的研究发现,磷脂酰肌醇-3-激酶(PI3K)及其下游的蛋白激酶B(又称AKT)、雷帕霉素靶蛋白(MTOR)组成的PI3K/AKT/MTOR信号通路在胃癌细胞的生长、分化、增殖、代谢、细胞骨架重组等一系列功能中发挥重要的作用,从而导致胃癌细胞凋亡或存活。针对PI3K/AKT/MTOR信号通路中各分子、蛋白的靶向抑制剂也在胃癌治疗中显示了一定的临床疗效。本文就PI3K/AKT/MTOR信号通路的发生机制,其在胃癌形成过程中的作用,以及通路相关抑制剂在胃癌中的研究进展作一综述。
引文
[1]Figueiredo C,Camargo MC,Leite M,et al.Pathogenesis of gastric cancer:genetics and molecular classification[J].Curr Top Microbiol Immunol,2017,400:277-304.
[2]Singh SS,Yap WN,Arfuso F,et al.Targeting the PI3K/Akt signaling pathway in gastric carcinoma:a reality for personalized medicine?[J].World J Gastroenterol,2015,21(43):12261-12273.
[3]Probst HC,Mc Coy K,Okazaki T,et al.Resting dendritic cells induce peripheral CD8+T cell tolerance through PD-1and CTLA-4[J].Nat Immunol,2005,6(3):280-286.
[4]O’Donnell JS,Massi D,MWL T,et al.PI3K-AKT-m TORinhibition in cancer immunotherapy,redux[J].Semin Cancer Biol,2018,48:91-103.
[5]Gu Y,Jin S,Wang F,et al.Clinicopathological significance of PI3K,Akt and survivin expression in gastric cancer[J].Biomed Pharmacother,2014,68(4):471-475.
[6]Suvarna V,Murahari M,Khan T,et al.Phytochemicals and PI3K inhibitors in cancer-an insight[J].Front Pharmacol,2017,8:916.
[7]Herschbein L,Liesveld JL.Dueling for dual inhibition:means to enhance effectiveness of PI3K/Akt/m TOR inhibitors in AML[J].Blood Rev,2018,32(3):235-248.
[8]Tran P,Nguyen C,Klempner SJ.Targeting the phosphatidylinositol-3-kinase pathway in gastric cancer:can omics improve outcomes?[J].Int Neurourol J,2016,20(Suppl 2):S131-S140.
[9]Brazil DP,Yang ZZ,Hemmings BA.Advances in protein kinase B signalling:AKTion on multiple fronts[J].Trends Biochem Sci,2004,29(5):233-242.
[10]Bae SS,Cho H,Mu J,et al.Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B[J].J Biol Chem,2003,278(49):49530-49536.
[11]Li J,Duan B,Guo Y,et al.Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and epirubicin by activating apoptosis and ameliorating P-glycoprotein activity[J].Biomed Pharmacother,2018,98:806-812.
[12]Zhang P,Su DM,Liang M,et al.Chemopreventive agents induce programmed death-1-ligand 1(PD-L1)surface expression in breast cancer cells and promote PD-L1-mediated t cell apoptosis[J].Mol Immunol,2008,45(5):1470-1476.
[13]Wan X,Helman LJ.The biology behind m TOR inhibition in sarcoma[J].Oncologist,2007,12(8):1007-1018.
[14]Sarbassov DD,Ali SM,Kim DH,et al.Rictor,a novel binding partner of m TOR,defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton[J].Curr Biol,2004,14(14):1296-1302.
[15]Carneiro BA,Kaplan JB,Altman JK,et al.Targeting m TOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia[J].Cancer Biol Ther,2015,16(5):648-656.
[16]Holz MK,Ballif BA,Gygi SP,et al.m TOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events[J].Cell,2005,123(4):569-580.
[17]Giguère V.Canonical signaling and nuclear activity of m TOR-a teamwork effort to regulate metabolism and cell growth[J].FEBS J,2018,285(9):1572-1588.
[18]Song Y,Li ZX,Liu X,et al.The Wnt/β-catenin and PI3K/Akt signaling pathways promote EMT in gastric cancer by epigenetic regulation via H3 lysine 27 acetylation[J].Tumour Biol,2017,39(7):1010428317712617.
[19]Cao GD,Chen K,Chen B,et al.Positive prognostic value of HER2-HER3 co-expression and p-m TOR in gastric cancer patients[J].BMC Cancer,2017,17(1):841.
[20]Chiappini PBO,de Medeiros IUD,Lima LGC,et al.Prognostic implications of phosphatidylinositol 3-kinase/AKTsignaling pathway activation in gastric carcinomas[J].Arch Med Sci,2017,13(6):1262-1268.
[21]Ishida K,Ito C,Ohmori Y,et al.Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil[J].Sci Rep,2017,7(1):2262.
[22]Sarker D,Ang JE,Baird R,et al.First-in-human phase Istudy of pictilisib(GDC-0941),a potent pan-class I phosphatidylinositol-3-kinase(PI3K)inhibitor,in patients with advanced solid tumors[J].Clin Cancer Res,2015,21(1):77-86.
[23]Hancox U,Cosulich S,Hanson L,et al.Inhibition of PI3Kβsignaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel[J].Mol Cancer Ther,2015,14(1):48-58.
[24]Barlaam B,Cosulich S,Degorce S,et al.Discovery of(R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide(AZD8186):a potent and selective inhibitor of PI3Kβand PI3Kδfor the treatment of PTEN-deficient cancers[J].JMed Chem,2015,58(2):943-962.
[25]Chien AJ,Cockerill A,Fancourt C,et al.A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies[J].Breast Cancer Res Treat,2016,155(3):521-530.
[26]Ramanathan RK,Mc Donough SL,Kennecke HF,et al.Phase 2 study of MK-2206,an allosteric inhibitor of AKT,as second-line therapy for advanced gastric and gastroesophageal junction cancer:a SWOG cooperative group trial(S1005)[J].Cancer,2015,121(13):2193-2197.
[27]Almhanna K,Strosberg J,Malafa M.Targeting AKT protein kinase in gastric cancer[J].Anticancer Res,2011,31(12):4387-4392.
[28]Davies BR,Greenwood H,Dudley P,et al.Preclinical pharmacology of AZD5363,an inhibitor of AKT:pharmacodynamics,antitumor activity,and correlation of monotherapy activity with genetic background[J].Mol Cancer Ther,2012,11(4):873-887.
[29]Zhang Y,Zheng Y,Faheem A,et al.A novel AKT inhibitor,AZD5363,inhibits phosphorylation of AKT downstream molecules,and activates phosphorylation of m TORand SMG-1 dependent on the liver cancer cell type[J].Oncol Lett,2016,11(3):1685-1692.
[30]Tamura K,Hashimoto J,Tanabe Y,et al.Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors[J].Cancer Chemother Pharmacol,2016,77(4):787-795.
[31]Yang H,Rudge DG,Koos JD,et al.m TOR kinase structure,mechanism and regulation[J].Nature,2013,497(448):217-223.
[32]Conciatori F,Ciuffreda L,Bazzichetto C,et al.m TORcross-talk in cancer and potential for combination therapy[J].Cancers(Basel),2018,10(1):E23.
[33]Doi T,Muro K,Boku N,et al.Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer[J].J Clin Oncol,2010,28(11):1904-1910.
[34]Takahari D.Second-line chemotherapy for patients with advanced gastric cancer[J].Gastric Cancer,2017,20(3):395-406.
[35]Kim ST,Lee J,Park SH,et al.Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy[J].BMC Cancer,2017,17(1):211.
[36]Fan Q,Aksoy O,Wong RA,et al.A kinase inhibitor targeted to m TORC1 drives regression in glioblastoma[J].Cancer Cell,2017,31:424-435.
[37]Cloughesy TF,Yoshimoto K,Nghiemphu P,et al.Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma[J].PLo SMed,2008,5(1):e8.
[38]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.
[39]Naing A,Aghajanian C,Raymond E,et al.Safety,tolerability,pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma[J].Br J Cancer,2012,107(7):1093-1099.
[40]Liu W,Chang J,Liu M,et al.Quantitative proteomics profiling reveals activation of m TOR pathway in trastuzumab resistance[J].Oncotarget,2017,8(28):45793-45806.
[41]Rodrik-Outmezguine VS,Okaniwa M,Yao Z,et al.Overcoming m TOR resistance mutations with a new-generation m TOR inhibitor[J].Nature,2016,534(7606):272-276.
[42]Zhang CΗ,Awasthi N,Schwarz MA,et al.The dual PI3K/m TOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer[J].Int JOncol,2013,43(5):1627-1635.
[43]Mueller A,Bachmann E,Linnig M,et al.Selective PI3Kinhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines[J].Cancer Chemother Pharmacol,2012,69(6):1601-1615.
[44]Zhu Y,Tian T,Zou J,et al.Dual PI3K/m TOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer[J].BMC Cancer,2015,15:894.
[45]Chakrabarty A,Rexer BN,Wang SE,et al.H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3[J].Oncogene,2010,29(37):5193-5203.
[46]Engelman JA,Luo J,Cantley LC.The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism[J].Nat Rev Genet,2006,7(8):606-619.
[47]Chakrabarty A,Sánchez V,Kuba MG,et al.Feedback upregulation of HER3(Erb B3)expression and activity attenuates antitumor effect of PI3K inhibitors[J].Proc Natl Acad Sci U S A,2012,109(8):2718-2723.
[48]Garrett JT,Sutton CR,Kurupi R,et al.Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110αinhibitor potently blocks PI3K signaling and growth of HER2+breast cancers[J].Cancer Res,2013,73(19):6013-6023.
[49]Abramson VG,Supko JG,Ballinger T,et al.Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors[J].Clin Cancer Res,2017,23(14):3520-3528.
[2]Singh SS,Yap WN,Arfuso F,et al.Targeting the PI3K/Akt signaling pathway in gastric carcinoma:a reality for personalized medicine?[J].World J Gastroenterol,2015,21(43):12261-12273.
[3]Probst HC,Mc Coy K,Okazaki T,et al.Resting dendritic cells induce peripheral CD8+T cell tolerance through PD-1and CTLA-4[J].Nat Immunol,2005,6(3):280-286.
[4]O’Donnell JS,Massi D,MWL T,et al.PI3K-AKT-m TORinhibition in cancer immunotherapy,redux[J].Semin Cancer Biol,2018,48:91-103.
[5]Gu Y,Jin S,Wang F,et al.Clinicopathological significance of PI3K,Akt and survivin expression in gastric cancer[J].Biomed Pharmacother,2014,68(4):471-475.
[6]Suvarna V,Murahari M,Khan T,et al.Phytochemicals and PI3K inhibitors in cancer-an insight[J].Front Pharmacol,2017,8:916.
[7]Herschbein L,Liesveld JL.Dueling for dual inhibition:means to enhance effectiveness of PI3K/Akt/m TOR inhibitors in AML[J].Blood Rev,2018,32(3):235-248.
[8]Tran P,Nguyen C,Klempner SJ.Targeting the phosphatidylinositol-3-kinase pathway in gastric cancer:can omics improve outcomes?[J].Int Neurourol J,2016,20(Suppl 2):S131-S140.
[9]Brazil DP,Yang ZZ,Hemmings BA.Advances in protein kinase B signalling:AKTion on multiple fronts[J].Trends Biochem Sci,2004,29(5):233-242.
[10]Bae SS,Cho H,Mu J,et al.Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B[J].J Biol Chem,2003,278(49):49530-49536.
[11]Li J,Duan B,Guo Y,et al.Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and epirubicin by activating apoptosis and ameliorating P-glycoprotein activity[J].Biomed Pharmacother,2018,98:806-812.
[12]Zhang P,Su DM,Liang M,et al.Chemopreventive agents induce programmed death-1-ligand 1(PD-L1)surface expression in breast cancer cells and promote PD-L1-mediated t cell apoptosis[J].Mol Immunol,2008,45(5):1470-1476.
[13]Wan X,Helman LJ.The biology behind m TOR inhibition in sarcoma[J].Oncologist,2007,12(8):1007-1018.
[14]Sarbassov DD,Ali SM,Kim DH,et al.Rictor,a novel binding partner of m TOR,defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton[J].Curr Biol,2004,14(14):1296-1302.
[15]Carneiro BA,Kaplan JB,Altman JK,et al.Targeting m TOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia[J].Cancer Biol Ther,2015,16(5):648-656.
[16]Holz MK,Ballif BA,Gygi SP,et al.m TOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events[J].Cell,2005,123(4):569-580.
[17]Giguère V.Canonical signaling and nuclear activity of m TOR-a teamwork effort to regulate metabolism and cell growth[J].FEBS J,2018,285(9):1572-1588.
[18]Song Y,Li ZX,Liu X,et al.The Wnt/β-catenin and PI3K/Akt signaling pathways promote EMT in gastric cancer by epigenetic regulation via H3 lysine 27 acetylation[J].Tumour Biol,2017,39(7):1010428317712617.
[19]Cao GD,Chen K,Chen B,et al.Positive prognostic value of HER2-HER3 co-expression and p-m TOR in gastric cancer patients[J].BMC Cancer,2017,17(1):841.
[20]Chiappini PBO,de Medeiros IUD,Lima LGC,et al.Prognostic implications of phosphatidylinositol 3-kinase/AKTsignaling pathway activation in gastric carcinomas[J].Arch Med Sci,2017,13(6):1262-1268.
[21]Ishida K,Ito C,Ohmori Y,et al.Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil[J].Sci Rep,2017,7(1):2262.
[22]Sarker D,Ang JE,Baird R,et al.First-in-human phase Istudy of pictilisib(GDC-0941),a potent pan-class I phosphatidylinositol-3-kinase(PI3K)inhibitor,in patients with advanced solid tumors[J].Clin Cancer Res,2015,21(1):77-86.
[23]Hancox U,Cosulich S,Hanson L,et al.Inhibition of PI3Kβsignaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel[J].Mol Cancer Ther,2015,14(1):48-58.
[24]Barlaam B,Cosulich S,Degorce S,et al.Discovery of(R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide(AZD8186):a potent and selective inhibitor of PI3Kβand PI3Kδfor the treatment of PTEN-deficient cancers[J].JMed Chem,2015,58(2):943-962.
[25]Chien AJ,Cockerill A,Fancourt C,et al.A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies[J].Breast Cancer Res Treat,2016,155(3):521-530.
[26]Ramanathan RK,Mc Donough SL,Kennecke HF,et al.Phase 2 study of MK-2206,an allosteric inhibitor of AKT,as second-line therapy for advanced gastric and gastroesophageal junction cancer:a SWOG cooperative group trial(S1005)[J].Cancer,2015,121(13):2193-2197.
[27]Almhanna K,Strosberg J,Malafa M.Targeting AKT protein kinase in gastric cancer[J].Anticancer Res,2011,31(12):4387-4392.
[28]Davies BR,Greenwood H,Dudley P,et al.Preclinical pharmacology of AZD5363,an inhibitor of AKT:pharmacodynamics,antitumor activity,and correlation of monotherapy activity with genetic background[J].Mol Cancer Ther,2012,11(4):873-887.
[29]Zhang Y,Zheng Y,Faheem A,et al.A novel AKT inhibitor,AZD5363,inhibits phosphorylation of AKT downstream molecules,and activates phosphorylation of m TORand SMG-1 dependent on the liver cancer cell type[J].Oncol Lett,2016,11(3):1685-1692.
[30]Tamura K,Hashimoto J,Tanabe Y,et al.Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors[J].Cancer Chemother Pharmacol,2016,77(4):787-795.
[31]Yang H,Rudge DG,Koos JD,et al.m TOR kinase structure,mechanism and regulation[J].Nature,2013,497(448):217-223.
[32]Conciatori F,Ciuffreda L,Bazzichetto C,et al.m TORcross-talk in cancer and potential for combination therapy[J].Cancers(Basel),2018,10(1):E23.
[33]Doi T,Muro K,Boku N,et al.Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer[J].J Clin Oncol,2010,28(11):1904-1910.
[34]Takahari D.Second-line chemotherapy for patients with advanced gastric cancer[J].Gastric Cancer,2017,20(3):395-406.
[35]Kim ST,Lee J,Park SH,et al.Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy[J].BMC Cancer,2017,17(1):211.
[36]Fan Q,Aksoy O,Wong RA,et al.A kinase inhibitor targeted to m TORC1 drives regression in glioblastoma[J].Cancer Cell,2017,31:424-435.
[37]Cloughesy TF,Yoshimoto K,Nghiemphu P,et al.Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma[J].PLo SMed,2008,5(1):e8.
[38]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.
[39]Naing A,Aghajanian C,Raymond E,et al.Safety,tolerability,pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma[J].Br J Cancer,2012,107(7):1093-1099.
[40]Liu W,Chang J,Liu M,et al.Quantitative proteomics profiling reveals activation of m TOR pathway in trastuzumab resistance[J].Oncotarget,2017,8(28):45793-45806.
[41]Rodrik-Outmezguine VS,Okaniwa M,Yao Z,et al.Overcoming m TOR resistance mutations with a new-generation m TOR inhibitor[J].Nature,2016,534(7606):272-276.
[42]Zhang CΗ,Awasthi N,Schwarz MA,et al.The dual PI3K/m TOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer[J].Int JOncol,2013,43(5):1627-1635.
[43]Mueller A,Bachmann E,Linnig M,et al.Selective PI3Kinhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines[J].Cancer Chemother Pharmacol,2012,69(6):1601-1615.
[44]Zhu Y,Tian T,Zou J,et al.Dual PI3K/m TOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer[J].BMC Cancer,2015,15:894.
[45]Chakrabarty A,Rexer BN,Wang SE,et al.H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3[J].Oncogene,2010,29(37):5193-5203.
[46]Engelman JA,Luo J,Cantley LC.The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism[J].Nat Rev Genet,2006,7(8):606-619.
[47]Chakrabarty A,Sánchez V,Kuba MG,et al.Feedback upregulation of HER3(Erb B3)expression and activity attenuates antitumor effect of PI3K inhibitors[J].Proc Natl Acad Sci U S A,2012,109(8):2718-2723.
[48]Garrett JT,Sutton CR,Kurupi R,et al.Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110αinhibitor potently blocks PI3K signaling and growth of HER2+breast cancers[J].Cancer Res,2013,73(19):6013-6023.
[49]Abramson VG,Supko JG,Ballinger T,et al.Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors[J].Clin Cancer Res,2017,23(14):3520-3528.