Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.

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Targeting epigenetic regulators is emerging as a promising strategy for cancer therapy. In this context, we recently identified the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) as a novel pCAF and GCN5 histone acetyltransferase inhibitor. CPTH6 exerts in vitro anti-tumoral effect in a panel of human tumor cell lines derived from different histotypes. In this study, we evaluated the efficacy of CPTH6 as a novel drug that targets Lung Cancer Stem-like Cells (LCSC) derived from non-small cell lung cancer (NSCLC) patients. We found that CPTH6 has a stronger growth-inhibitory effect in patient-derived LCSC than in established NSCLC lines. Unlike LCSC models, in which CPTH6 treatment induces cell cycle perturbation and apoptosis even at low doses, in established NSCLC lines CPTH6 triggers a cell cycle perturbation associated to DNA damage only at higher concentrations. Of note, differentiated progeny of LCSC lines are more resistant to CPTH6 cytoxicity when compared to their undifferentiated counterparts. Interestingly, CPTH6 treatment is also associated with reduced expression of the CD133 stemness marker in LCSC lines. Analysis of the CD133+ subpopulation in LCSC lines indicates that CD133+ cells not only undergo apoptosis following CPTH6 treatment but also shift toward a more differentiated phenotype. Furthermore, the growth inhibitory effect seems to be tightly related to baseline expression of acetylated alpha-tubulin, which was particularly prominent in sensitive LCSC lines. In vivo experiments confirmes the antitumor efficacy of CPTH6, particularly in LCSC-derived models, where a pronounced apoptosis induction and growth inhibitory effect is observed after CPTH6 treatment. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC. Citation Format: Marta Di Martile, Mariannna Desideri, Teresa De Luca, Chiara Gabellini, Adriana Eramo, Michele Milella, Daniela Secci, Simone Carradori, Simona Buglioni, Donatella Del Bufalo, Daniela Trisciuoglio. The histone acetyltransferase inhibitor CPTH6 selectively targets lung cancer stem-like cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2324. doi:10.1158/1538-7445.AM2015-2324