CDKN1A upregulation and cisplatin-pemetrexed resistance in non-small cell lung cancer cells

Abstract

Cisplatin-pemetrexed is a frequently adopted first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) ineligible for biological therapy, notwithstanding its limited efficacy. In the present study, the RAL cell line, an epidermal growth factor receptor ( EGFR)-wild-type, p53- and KRAS-mutated model of NSCLC, was used to investigate novel biomarkers of resistance to this treatment. Cells were analyzed 96 h (96 h-post wo) and 21 days (21 days-post wo) after the combined treatment washout. Following an initial moderate sensitivity to the treatment, the cell growth proliferative capability had fully recovered. Gene expression analysis of the resistant surviving cells revealed a significant upregulation of CDKN1A expression in the cells at 96-h post-wo and, although to a lesser extent, in the cells at 21 days-post wo, accompanied by an enrichment of acetylated histone H3 in its promoter region. CDKN1A was also upregulated at the protein level, being mainly detected in the cytoplasm of the cells at 96 h-post wo. A marked increase in the number of apoptotic cells, together with a significant G1 phase block, were observed at 96-h post wo in the cells in which CDKN1A was knocked down, suggesting its involvement in the modulation of the response of RAL cells to the drug combination. On the whole, these data suggest that CDKN1A plays a role in the response to the cisplatin-pemetrexed combination in advanced KRAS-mutated NSCLC, thus suggesting that it may be used as a promising predictive marker.