Bouali Sanae, Chrétien Anne-Sophie, Ramacci Carole, Rouyer Marie, Becuwe Philippe, Merlin Jean-Louis
Centre Alexis Vautrin, Unité de Biologie des Tumeurs, 54511 Vandaeuvre-lès-Nancy Cedex, France.
Oncol Rep. 2009 Mar;21(3):731-5.
Overexpression of epidermal growth factor receptor (EGFR) and mutation of pten tumor suppressor gene in human cancer cells leads to activated EGFR downstream signaling including PI3-kinase/AKT (PI3K/AKT) and/or mitogen-activated protein kinases (RAS/RAF/MAPK) and have been linked to resistance to anti-EGFR targeted therapies. Cetuximab is a chimeric IgG1 monoclonal antibody that binds the EGFR with high specificity and have been developed as promising therapeutic anticancer treatments in several solid tumors, including colorectal and head and neck squamous cell carcinomas. Cetuximab activity is related to PI3K/AKT and RAS/RAF/MAPK signaling pathways functionality and its activity has been shown to be higher in wild-type KRAS tumors. To study the influence of PTEN expression on cell response to cetuximab, we used wild-type KRAS, PTEN-null, EGFR overexpressing PC3 prostate cancer cells. Reintroduction of PTEN significantly reduced the constitutive overexpression of phosphorylated-AKT (p-AKT) and downstream kinases (p-GSK3beta and p-P70S6 kinase) as well as phosphorylated-ERK1/2 (p-ERK1/2) and consequently significantly restored cetuximab-induced cell growth inhibition and apoptosis induction. Taken together, the results achieved in the present study show that PTEN controls the cellular response to cetuximab in KRAS wild-type prostate carcinoma PC3 cells through the regulation of AKT phosphorylation and restoration of the functionality of EGFR downstream signaling. Extrapolation of these findings to clinical situation, suggests that the assessment of EGFR downstream signaling functionality could be proposed as a diagnostic response predictive marker for anti-EGFR targeted therapies.
人类癌细胞中表皮生长因子受体（EGFR）的过表达和抑癌基因pten的突变会导致EGFR下游信号通路激活，包括PI3激酶/AKT（PI3K/AKT）和/或丝裂原活化蛋白激酶（RAS/RAF/MAPK），并且与抗EGFR靶向治疗的耐药性相关。西妥昔单抗是一种嵌合IgG1单克隆抗体，它能高度特异性地结合EGFR，并已被开发用于多种实体瘤的有前景的抗癌治疗，包括结直肠癌和头颈部鳞状细胞癌。西妥昔单抗的活性与PI3K/AKT和RAS/RAF/MAPK信号通路的功能有关，并且已证明其在野生型KRAS肿瘤中的活性更高。为了研究PTEN表达对细胞对西妥昔单抗反应的影响，我们使用了野生型KRAS、PTEN缺失、EGFR过表达的PC3前列腺癌细胞。重新引入PTEN显著降低了磷酸化-AKT（p-AKT）和下游激酶（p-GSK3β和p-P70S6激酶）以及磷酸化-ERK1/2（p-ERK1/2）的组成型过表达，因此显著恢复了西妥昔单抗诱导的细胞生长抑制和凋亡诱导。综上所述，本研究取得的结果表明，PTEN通过调节AKT磷酸化和恢复EGFR下游信号通路的功能来控制KRAS野生型前列腺癌PC3细胞对西妥昔单抗的细胞反应。将这些发现外推至临床情况，提示EGFR下游信号通路功能的评估可作为抗EGFR靶向治疗的诊断反应预测标志物。
