The predictive value of ERCC1 and p53 for the effect of panobinostat and cisplatin combination treatment in NSCLC

// Yang Cai 1 , Xiang Yan 1 , Guoqing Zhang 1 , Weihong Zhao 1 , Shunchang Jiao 1 1 Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China Correspondence to: Shunchang Jiao, e-mail: jiaosc@vip.sina.com Keywords: panobinostat, cisplatin, ERCC1, gain of function mutant p53, NSCLC Received: February 16, 2015      Accepted: April 17, 2015      Published: April 29, 2015 ABSTRACT Cisplatin is one of the most common chemotherapeutic drugs for non-small cell lung cancer (NSCLC). However, the response rate is limited because of drug resistance. Histone deacetylase inhibitors (HDACis), which can alter DNA accessibility by regulating chromatin structure and inducing apoptosis, exhibit a synergistic action with cisplatin. However, no biomarkers that can predict the efficacy of the combination of HDACis and cisplatin have been reported. Our study found that panobinostat, an HDAC inhibitor, increased the cisplatin sensitivity of several NSCLC cell lines with low ERCC1 expression but not those with high ERCC1 expression or gain-of-function (GOF) p53 mutation despite of ERCC1 expression level. ERCC1 knockdown increased the cisplatin sensitivity of NSCLC cell lines with high ERCC1 expression without GOF p53 mutations. In addition, in low ERCC1 expression NSCLC cell lines, knockdown of GOF mutant p53 enhanced cisplatin sensitivity. Further double knockdown of ERCC1 and GOF mutant p53 but not ERCC1 knockdown alone increased the cisplatin sensitivity of cells with both high ERCC1 expression and GOF p53 mutations. Therefore, this study demonstrated that ERCC1 expression combined with p53 mutation status may determine the efficacy of cisplatin and HDACi combined therapy and guide the development of future NSCLC therapies.