Tsurutani Junji, West Kip A, Sayyah Jacqueline, Gills Joell J, Dennis Phillip A
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
Cancer Res. 2005 Sep 15;65(18):8423-32. doi: 10.1158/0008-5472.CAN-05-0058.
The fact that small cell lung cancer (SCLC) is commonly incurable despite being initially responsive to chemotherapy, combined with disappointing results from a recent SCLC clinical trial with imatinib, has intensified efforts to identify mechanisms of SCLC resistance. Adhesion to extracellular matrix (ECM) is one mechanism that can increase therapeutic resistance in SCLC cells. To address whether adhesion to ECM increases resistance through modulation of signaling pathways, a series of SCLC cell lines were plated on various ECM components, and activation of two signaling pathways that promote cellular survival, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway, was assessed. Although differential activation was observed, adhesion to laminin increased Akt activation, increased cellular survival after serum starvation, and caused the cells to assume a flattened, epithelial morphology. Inhibitors of the PI3K/Akt/mTOR pathway (LY294002, rapamycin) but not the MEK/ERK pathway (U0126) abrogated laminin-mediated survival. SCLC cells plated on laminin were not only resistant to serum starvation-induced apoptosis but were also resistant to apoptosis caused by imatinib. Combining imatinib with LY294002 or rapamycin but not U0126 caused greater than additive increases in apoptosis compared with apoptosis caused by the inhibitor or imatinib alone. Similar results were observed when adenoviruses expressing mutant Akt were combined with imatinib, or when LY294002 was combined with cisplatin or etoposide. These studies identify laminin-mediated activation of the PI3K/Akt/mTOR pathway as a mechanism of cellular survival and therapeutic resistance in SCLC cells and suggest that inhibition of the PI3K/Akt/mTOR pathway is one strategy to overcome SCLC resistance mediated by ECM.
尽管小细胞肺癌（SCLC）最初对化疗有反应，但通常无法治愈，再加上最近一项使用伊马替尼的SCLC临床试验结果令人失望，这使得人们更加努力地去寻找SCLC耐药的机制。与细胞外基质（ECM）的黏附是一种可增加SCLC细胞治疗耐药性的机制。为了研究与ECM的黏附是否通过调节信号通路来增加耐药性，将一系列SCLC细胞系接种在各种ECM成分上，并评估促进细胞存活的两条信号通路——磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶点（mTOR）通路和丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（MEK/ERK）通路的激活情况。尽管观察到了不同的激活情况，但与层粘连蛋白的黏附增加了Akt的激活，增加了血清饥饿后的细胞存活，并使细胞呈现扁平的上皮形态。PI3K/Akt/mTOR通路的抑制剂（LY294002、雷帕霉素）而非MEK/ERK通路的抑制剂（U0126）消除了层粘连蛋白介导的细胞存活。接种在层粘连蛋白上的SCLC细胞不仅对血清饥饿诱导的凋亡有抗性，而且对伊马替尼引起的凋亡也有抗性。与单独使用抑制剂或伊马替尼引起的凋亡相比，将伊马替尼与LY294002或雷帕霉素而非U0126联合使用可导致凋亡增加幅度大于相加效应。当表达突变型Akt的腺病毒与伊马替尼联合使用时，或者当LY294002与顺铂或依托泊苷联合使用时，也观察到了类似的结果。这些研究确定层粘连蛋白介导的PI3K/Akt/mTOR通路激活是SCLC细胞中细胞存活和治疗耐药的一种机制，并表明抑制PI3K/Akt/mTOR通路是克服由ECM介导的SCLC耐药的一种策略。
