Thomas Gaëlle, Chardès Thierry, Gaborit Nadège, Mollevi Caroline, Leconet Wilhem, Robert Bruno, Radosevic-Robin Nina, Penault-Llorca Frédérique, Gongora Céline, Colombo Pierre-Emmanuel, Lazrek Yassamine, Bras-Goncalves Rui, Savina Ariel, Azria David, Bazin Hervé, Pèlegrin André, Larbouret Christel
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France. Institut Roche de Recherche et Médecine Translationnelle, Boulogne Bilancourt, France.
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, Unit 896, Montpellier, F-34298, France; Université Montpellier1, Montpellier, F-34298, France; ICM, Montpellier, France.
Oncotarget. 2014 Aug 30;5(16):7138-48. doi: 10.18632/oncotarget.2231.
The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.
抗HER2抗体帕妥珠单抗可抑制HER2二聚化，并影响HER2/HER3二聚体的形成及信号传导。由于HER3及其配体神经调节蛋白与胰腺肿瘤发生有关，我们研究了HER3表达是否可能是帕妥珠单抗在HER2低表达胰腺癌中疗效的预测生物标志物。我们将体外和体内的HER3表达及神经调节蛋白依赖性与帕妥珠单抗对细胞活力和肿瘤进展的抑制作用进行了关联分析。在BxPC-3细胞中敲低HER3导致对帕妥珠单抗治疗产生耐药性。用帕妥珠单抗处理表达HER3的胰腺癌细胞可使细胞膜上的HER3增加，而抗HER3单克隆抗体9F7-F11则使其下调。两种抗体均阻断HER3和AKT磷酸化，并抑制HER2/HER3异二聚化，但对HER2和HER3同二聚体的影响不同。帕妥珠单抗/9F7-F11联合用药增强了对移植有表达HER3的胰腺癌细胞的小鼠的肿瘤抑制作用及中位生存时间。最后，在通过免疫组织化学分析 的45例胰腺导管腺癌中，11%同时表达HER2和HER3，27%仅表达HER3。HER3对于帕妥珠单抗在HER2低表达胰腺癌中的疗效至关重要，HER3表达可能是此类癌症中帕妥珠单抗疗效的预测生物标志物。需要对临床样本进行进一步研究以证实这些发现以及联合使用抗HER2和抗HER3治疗性抗体的意义。
