Abstract 974: Elucidating the synergistic action of histone deacetylase inhibitor and cisplatin in lung squamous cell carcinoma.
Authors: Kong Li Ren , Chua Kian Ngiap , Wang Lingzhi , Chng Wee Joo , Goh Boon Cher 
Published: August 2014

Non-small cell lung cancer (NSCLC) constitutes 85-90% of all lung cancer cases with squamous cell carcinoma (SCC) being one of the major subtypes of NSCLC (35%). Although the risk of developing lung SCC remains steadfast in recent years, it prevails as a major public health concern worldwide due to its low 5-year overall survival rate. Platinum-based chemotherapies are currently the standard of care NSCLC, however, resistance to platinum compounds pose to be a major obstacle in achieving long term therapeutic effects. Currently, the understanding on resistance in lung SCC is severely limited. While many targeted therapies have been recently approved for adenocarcinoma of the lung, only a limited few have been applied on lung SCC due to a paucity of identifiable driver mutations. Hence, elucidation of specific pathways responsible for platinum resistance may reveal novel chemotherapeutic targets aimed at circumventing resistance to platinum in lung SCC. From a panel of lung SCC cell lines, we categorized them into cisplatin-resistant and -sensitive groups as study models based on cell viability assays. Gene expression profiles in these models after cisplatin treatment revealed that genes involved in MAPK signalling pathway and phosphatidylinositol signalling system were down-regulated in the cisplatin-sensitive group. Further investigation utilizing phosphoprotein antibody arrays revealed changes to levels of phosphorylated signalling proteins, with phosphorylated Akt, Erk1/2, p38, GSK3 and RSK levels abrogated upon cisplatin treatment in a sensitive cell line. In contrast, elevated levels of phosphorylated Erk1/2 were observed in a resistant cell line, suggesting the involvement of Erk in cisplatin resistance. Inhibitors of histone deacetylase (HDAC) have been shown to induce differentiation, cell growth arrest, and apoptosis in NSCLC cells. Recent reports have demonstrated that HDAC inhibitors could re-sensitize tumours to chemotherapy, but the mechanism(s) for these observations remains unknown. Here, we observed that cisplatin-resistant SCC lines were more responsive towards PXD101, a pan-HDAC inhibitor. Interestingly, we observed that PXD101 selectively dephosphorylated Erk1/2 and GSK3α/β, but had no activity on phosphorylated Akt. Moreover, several SCC lines grown under anchorage-independent growth condition demonstrated that treatment with HDAC inhibitor could suppress the malignant growth of transformed cells in combination with cisplatin. Taken together, these results illustrate the synergistic effects of HDAC inhibitor in cisplatin-resistant lung SCC tumours. Our preliminary findings also convey that Erk1/2 could be a potential target for the treatment of lung SCC tumours with intrinsic resistance to cisplatin.

Citation Format: Li Ren Kong, Kian Ngiap Chua, Lingzhi Wang, Wee Joo Chng, Boon Cher Goh. Elucidating the synergistic action of histone deacetylase inhibitor and cisplatin in lung squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 974. doi:10.1158/1538-7445.AM2013-974