Cufí Sílvia, Vazquez-Martin Alejandro, Oliveras-Ferraros Cristina, Corominas-Faja Bruna, Cuyàs Elisabet, López-Bonet Eugeni, Martin-Castillo Begoña, Joven Jorge, Menendez Javier A
1] Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology-Girona (ICO-Girona), Girona, Spain [2] Molecular Oncology, Girona Biomedical Research Institute (IDIBGi), Girona, Spain [3].
Sci Rep. 2013;3:2469. doi: 10.1038/srep02469.
Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer.
自噬可能控制HER2基因扩增的乳腺癌对单克隆抗体曲妥珠单抗（赫赛汀）的原发性耐药。最初从一名一开始使用曲妥珠单抗就迅速进展的患者身上获取的肿瘤细胞，显示出细胞中LC3-II蛋白水平升高——这一发现与自噬体数量增加相关——以及自噬受体p62/SQSTM1水平降低，p62/SQSTM1是一种被自噬选择性降解的蛋白质。曲妥珠单抗耐药细胞处于“自噬成瘾”状态，因为自噬特异性基因（ATG8、ATG5、ATG12）的基因消融显著降低了对曲妥珠单抗的固有耐药性。当抗疟疾溶酶体药物氯喹阻碍曲妥珠单抗存在时形成的自噬溶酶体积累的自噬降解时，细胞会通过凋亡死亡。因此，在对曲妥珠单抗完全耐药的肿瘤异种移植模型中，曲妥珠单抗与氯喹联合治疗可使肿瘤生长显著抑制>90%。因此，在基于曲妥珠单抗的治疗方案中添加氯喹可能会改善自噬成瘾的HER2阳性乳腺癌女性的治疗效果。
