title: The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer.
abstract: 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.
authors: 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].
authors: Sílvia
authors: S
authors: Cufí
authors: Alejandro
authors: A
authors: Vazquez-Martin
authors: Cristina
authors: C
authors: Oliveras-Ferraros
authors: Bruna
authors: B
authors: Corominas-Faja
authors: Elisabet
authors: E
authors: Cuyàs
authors: Eugeni
authors: E
authors: López-Bonet
authors: Begoña
authors: B
authors: Martin-Castillo
authors: Jorge
authors: J
authors: Joven
authors: Javier A
authors: JA
authors: Menendez
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D010588:Phagosomes / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000962:Antimalarials; D000970:Antineoplastic Agents; D053148:Caspase 3; D002738:Chloroquine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
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