Abstract C54: The identification of cisplatin resistance pathways in lung squamous cell carcinoma and approaches to overcome resistance
Authors: Li Ren Kong, Lingzhi Wang, Seow Ching Wan, Jieying Amelia Lau, Pei Ling Nye, Thuya Win Lwin, Boon Cher Goh
Journal: Cancer Research (2011)

Abstract Cisplatin, a commonly used chemotherapeutic agent, has been extensively used in the treatment of lung squamous cell carcinoma (SCC). Despite its strong efficacy in the treatment of SCC, resistance often developed in patients resulting in a major obstacle in lung cancer therapeutics. Different types of tumours with varying response to cisplatin lead to the proposal of various cisplatin resistance pathways, which consequently hinders the identification of a universal molecular mechanism of therapeutic resistance to cisplatin. In this study, we focus on cisplatin-resistance pathway with respect to lung SCC. Histone deacetylase (HDAC) inhibitors have been shown to sensitize drug-resistant cells to various anti-cancer agents. We showed that PXD101, a HDAC inhibitor, abrogrates cisplatin resistance in lung SCC cells. Our preliminary screening suggested a differential sensitivity of a panel often lung SCC cells to cisplatin and PXD101. Combination index studies showed that cisplatin-resistant cells developed better sensitivity towards PXD101 treatment, and displayed a better synergism in cisplatin-PXD101 combination treatment. Furthermore, we observed differences in gene expression profiles in both cisplatin-sensitive and resistant cells, as well as the respective responses towards cisplatin treatment. The data here revealed that compare to cisplatin-sensitive cells, cisplatin-resistant cells induced a higher expression of drug detoxification-related genes and a lower expression of apoptosis related genes. TP53INP1, a p53 targeting gene that induces p53 transcriptional activities, was up-regulated in cisplatin-sensitive cells upon cisplatin treatment, along with the down-regulation of genes related to PI3K-Akt-mTOR and MAPK pathways. On the contrary, cisplatin treatment had no significant effect on the genetic expression of cisplatin-resistant cells. Results here suggest that cisplatin sensitivity might be related to a p53-dependent pathway. Inactivation of cell death is a critical step in tumour progression, and p53, a tumour suppressor gene that is mutated in 80% of SCC patients, is an important mediator of cell death. We therefore selected a cisplatin-resistant, PXD101-sensitive, p53 mutant cell line to study the potential roles of PXD101 and cisplatin in p53-regulated cell death. A low concentration of PXD101, which alone exhibits little cytotoxicity, markedly enhanced the induction of apoptotic cell death by cisplatin. We showed that the expression of both mRNA and protein of the apoptotic regulators were modulated upon combination treatment, suggesting that the apoptosis could be activated at the transcriptional level. While all treatments did not affect the endogenous level of p53, we observed that combination treatment markedly potentiated the post-translational acetylations of p53 molecule and these acetylations were more specific to nuclear p53. Taken together, these results suggest that combination treatment of PXD101 and cisplatin is a potent chemotherapeutic strategy for the eradication of cisplatin-resistant tumours, possibly via the transcriptional-dependent p53 pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C54.