title: STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer.
abstract: The signal transducer and activator of transcription 3 (STAT3) has been suggested to play a prominent role in mediating non-small-cell lung cancer (NSCLC) resistance to some tyrosine kinase inhibitor (TKI)-mediated therapies. Using a model of anaplastic lymphoma kinase gene (ALK)-translocated NSCLC with acquired resistance to the ALK TKI crizotinib, but lacking amplifications or mutations in the kinase domain of ALK, we herein present evidence that STAT3 activation is a novel mechanism of crizotinib resistance that involves the upregulation of immune escape and epithelial to mesenchymal transition (EMT) signaling pathways. Taking advantage of the flavonolignan silibinin as a naturally occurring STAT3-targeted pharmacological inhibitor, we confirmed that STAT3 activation protects ALK-translocated NSCLC from crizotinib. Accordingly, silibinin-induced inhibition of STAT3 worked synergistically with crizotinib to reverse acquired resistance and restore sensitivity in crizotinib-resistant cells. Moreover, silibinin treatment significantly inhibited the upregulation of the immune checkpoint regulator PD-L1 and also EMT regulators (e.g., SLUG, VIM, CD44) in crizotinib-refractory cells. These findings provide a valuable strategy to potentially improve the efficacy of ALK inhibition by cotreatment with silibinin-based therapeutics, which merit clinical investigation for ALK TKI-resistant NSCLC patients.
authors.affiliation: a Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.|b Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI) , Girona , Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: c Molecular and Cell Biology Institute, Miguel Hernández University , Elche , Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Pérez-Sánchez
authors.affiliation: c Molecular and Cell Biology Institute, Miguel Hernández University , Elche , Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Micol
authors.affiliation: a Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.|b Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI) , Girona , Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: b Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI) , Girona , Spain.|d Deparment of Medical Oncology , Catalan Institute of Oncology , Girona , Catalonia , Spain.|e Department of Medical Sciences , Medical School, University of Girona , Girona , Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D060890:B7-H1 Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D050796:STAT3 Transcription Factor; D012838:Silymarin; D000077385:Silybin; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; EMT; STAT3; crizotinib; lung cancer; silibinin