Saturno Grazia, Valenti Melanie, De Haven Brandon Alexis, Thomas George V, Eccles Suzanne, Clarke Paul A, Workman Paul
Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
Oncotarget. 2013 Aug;4(8):1185-98. doi: 10.18632/oncotarget.1162.
TRAIL has been shown to induce apoptosis in cancer cells, but in some cases they fail to respond to this ligand. We explored the ability of representative phosphatidylinositol-3-kinase (PI3 Kinase)/mTOR and HSP90 inhibitors to overcome TRAIL resistance by increasing apoptosis in colorectal cancer models. We determined the sensitivity of 27 human colorectal cancer and 2 non-transformed colon epithelial cell lines to TRAIL treatment. A subset of the cancer cell lines with a range of responses to TRAIL was selected from the panel for treatment with TRAIL combined with the PI3 Kinase/mTOR inhibitor PI-103 or the HSP90 inhibitor 17-AAG (tanespimycin). Two TRAIL-resistant cell lines were selected for in vivo combination studies with TRAIL and 17-AAG. We found that 13 colorectal cancer cell lines and the 2 non-transformed colon epithelial cell lines were resistant to TRAIL. We demonstrated that co-treatment of TRAIL and PI-103 or 17-AAG was synergistic or additive and significantly enhanced apoptosis in colorectal cancer cells. This was associated with decreased expression or activity of survival protein biomarkers such as ERBB2, AKT, IKKα and XIAP. In contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We show here for the first time that co-treatment in vivo with TRAIL and 17-AAG in two TRAIL-resistant human colorectal cancer xenograft models resulted in significantly greater tumor growth inhibition compared to single treatments. We propose that combining TRAIL with PI3 Kinase/mTOR or HSP90 inhibitors has therapeutic potential in the treatment of TRAIL-resistant colorectal cancers.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）已被证明可诱导癌细胞凋亡，但在某些情况下，癌细胞对这种配体没有反应。我们研究了代表性的磷脂酰肌醇-3-激酶（PI3激酶）/雷帕霉素靶蛋白（mTOR）和热休克蛋白90（HSP90）抑制剂通过增加大肠癌细胞凋亡来克服TRAIL耐药性的能力。我们测定了27种人结肠癌细胞系和2种未转化的结肠上皮细胞系对TRAIL治疗的敏感性。从该细胞系库中选择了一组对TRAIL有不同反应的癌细胞系，用TRAIL联合PI3激酶/mTOR抑制剂PI-103或HSP90抑制剂17-AAG（坦螺旋霉素）进行治疗。选择了两种TRAIL耐药细胞系进行TRAIL与17-AAG的体内联合研究。我们发现13种结肠癌细胞系和2种未转化的结肠上皮细胞系对TRAIL耐药。我们证明，TRAIL与PI-103或17-AAG联合治疗具有协同或相加作用，并显著增强了大肠癌细胞的凋亡。这与生存蛋白生物标志物如ERBB2、AKT、IKKα和X连锁凋亡抑制蛋白（XIAP）的表达或活性降低有关。相比之下，联合治疗对未转化结肠细胞的影响最小。我们首次在此表明，在两种TRAIL耐药的人结肠直肠癌异种移植模型中，TRAIL与l7-AAG联合体内治疗比单一治疗能显著抑制肿瘤生长。我们提出，将TRAIL与PI3激酶/mTOR或HSP90抑制剂联合使用在治疗TRAIL耐药的结肠直肠癌方面具有治疗潜力。
