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.Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancers and remains the leading cause of cancerrelated deaths worldwide. Molecular driver mutations such as KRAS and epidermal growth factor receptor (EGFR) play an important role in lung tumorigenesis, and is therefore could be an attractive target for personalized therapy. The EGFRtyrosine kinase inhibitors (EGFR-TKIs) have shown efficacy in NSCLC patients, especially those harboring activating mutations in the EGFR. 1 However, an acquired secondary mutation in the EGFR (T790M) or the somatic mutation in KRAS results in resistance to EGFR-TKIs. Moreover, KRAS mutations in EGFR-wild type NSCLC patients lost efficacy to EGFR-TKIs and front-line chemotherapy. 2,3 Thus, elucidating compensatory signaling would be a considerable approach to identify therapeutic targets and overcome the resistance.Histone deacetylase inhibitors (HDACis) are promising antitumor agents by globally attenuating acetylation events and blocking several cancer-related signaling pathways. Among these, panobinostat (LBH589) has been extensively studied against a wide variety of hematological and solid malignancies, and was approved for treating multiple myelomas in the clinic. 4 Panobinostat showed potentiality against several cancer types including NSCLC, 5-7 and increased efficacy when in combination with chemotherapy or radiotherapy
The tumor microenvironment plays an important role in tumor initiation and progression. It is well documented that nicotine participates in cigarette smoking-related malignancies. Previous studies focused on the effects of nicotine on tumor cells; however, the role of the microenvironment in nicotine-mediated tumorigenesis is poorly understood. Herein, we investigated the effect and molecular mechanism of nicotine on fibroblasts and its contribution to breast cancer. We found that nicotine induced the epithelial-mesenchymal transition (EMT) of breast cancer cells and promoted activation of fibroblasts. Interestingly, conditioned medium from nicotine-activated fibroblasts (Nic-CM) had a greater impact on promoting the EMT and migratory capability toward cancer cells than did treatment with nicotine alone. Production of connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β by nicotine-treated fibroblasts was demonstrated to be crucial for promoting the EMT and cancer cell migration, and blocking of CTGF and TGF-β in Nic-CM-suppressed tumor motility. Moreover, nicotine induced expressions of CTGF, and TGF-β in fibroblasts as identified through α7 nicotinic acetylcholine receptor (nAChR)-dependent activation of the AKT/TAZ signaling mechanism. Together, our data showed for the first time that activation of fibroblasts is largely responsible for accelerating smoking-mediated breast cancer progression.
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