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Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ
Author(s) -
Lee WenYing,
Chen PinCyuan,
Wu WenShin,
Wu HanChung,
Lan ChunHsin,
Huang YenHua,
Cheng ChiaHsiung,
Chen KuChung,
Lin ChengWei
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30888
Subject(s) - gefitinib , kras , panobinostat , cancer research , epidermal growth factor receptor , medicine , lung cancer , cancer , oncology , biology , histone deacetylase , colorectal cancer , histone , biochemistry , gene
Mutation of KRAS in non‐small‐cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti‐KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of panobinostat against gefitinib‐resistant NSCLC is unclear. In this study, we demonstrated that panobinostat overcame resistance to gefitinib in KRAS‐mutant/EGFR‐wild‐type NSCLC. Combined panobinostat and gefitinib synergistically reduced tumor growth in vitro and in vivo . Mechanistically, we identified that panobinostat—but not gefitinib—inhibited TAZ transcription, and the combination of panobinostat and gefitinib synergistically downregulated TAZ and TAZ downstream targets, including EGFR and EGFR ligand. Inhibition of TAZ by panobinostat or short hairpin RNA sensitized KRAS‐mutant/EGFR‐wild‐type NSCLC to gefitinib through abrogating AKT/mammalian target of rapamycin (mTOR) signaling. Clinically, TAZ was positively correlated with EGFR signaling, and coexpression of TAZ/EGFR conferred a poorer prognosis in lung cancer patients. Our findings identify that targeting TAZ‐mediated compensatory mechanism is a novel therapeutic approach to overcome gefitinib resistance in KRAS‐mutant/EGFR‐wild‐type NSCLC.