Journal
CELL CYCLE
Volume 15, Issue 24, Pages 3413-3418Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2016.1245249
Keywords
ALK; crizotinib; EMT; lung cancer; silibinin; STAT3
Categories
Funding
- Ministerio de Ciencia e Innovacion [SAF2012-38914]
- Plan Nacional de I+D+I, Spain
- Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR), Departament d'Economia I Coneixement, Catalonia, Spain [2014 SGR229]
- Ministerio de Sanidad y Consumo, Fondo de Investigacion Sanitaria (FIS), Spain [CD15/00033]
- Spanish Society of Medical Oncology (SEOM, Madrid, Spain)
- Pfizer [WI190764]
- VALiCd fellowship [ACIF/2013/064]
- [PROMETEO/2016/006]
- [AGL2015-67995-C3-1-R]
- [CIBERobn CB12/03/30038]
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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.
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