Abstract 2558: The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC)

Abstract

Platinum-based chemotherapy is conventionally the first line treatment for EGFR wild type patients while EGFR-TKI is the standard for patients with mutation. Subgroup biomarker studies conducted in FASTACT-2 (Wu et al Lancet Oncology 2013) indicated that patients with positive ERCC1 attained longer overall survival and progression free survival under intercalated chemotherapy and EGFR-TKI, in comparison with solely chemotherapy. EGFR-TKI is postulated to down-regulate ERCC1 expression in EGFR wild type NSCLC cells, hence enhancing the Chemo efficacy. The study aims to investigate the missing link between EGFR and ERCC1 in the perspective of mechanistic means. In vitro and in vivo studies were devised to examine the impact imposed on ERCC1 by EGFR-TKI. H1993 cells underwent a 72-hour EGFR-TKI treatment and transient siRNA transfection for ERCC1 suppression. Cell viability assay was employed for detecting the cisplatin sensitivity of the transfected cells. Xenograft tumor models were established with a 2-week treatment of oral erlotinib on animals, using western blot and IHC to study the ERCC1 expression. Human EGFR Phosphorylation Membrane Array was used to study the EGFR phosphorylation pattern involved in ERCC1 level alterations and its downstream pathways were further analyzed with western blot. ERCC1 expression level is not correlated with EGFR-TKI sensitivity. Nonetheless, ERCC1 level gradually decreased along the 72-hour exposure of EGFR-TKI. The cells’ sensitivity towards cisplatin was raised upon ERCC1 knock-down with its IC50 reduced from 14.67μM to 0.16μM. Furthermore, TKI showed a significant reduction in ERCC1 level with IHC staining after treatment yet no sequel on the tumor volume of the xenografts. On the mechanistic side, 6 out of 17 EGFR phosphorylation sites were found compelling in respond to variations on ERCC1 level. We discovered that the MAPK/ERK and JNK pathways were the potential candidates that regulated EGFR associated ERCC1 expression. In summary, the data manifested that EGFR-TKI may reduce ERCC1 expression and latently enhance sensitivity towards cisplatin. MAPK/ERK and JNK pathways may contribute in ERCC1 regulation. With the preliminary screening results, it warrants further investigation to validate the underlying mechanism for the regulation of ERCC1 expression level. Citation Format: Hio Teng Cheong, Connie Wun Chun Hui, Fei Xu, Tony Shu Kam Mok, Chi Hang Wong. The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC). [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 2558. doi:10.1158/1538-7445.AM2015-2558

Effects of p38MAPK-mediated excision repair cross-complementation 1 expression on prognosis of patients with non-small cell lung cancer

“…Platinum-based two-drug combined chemotherapy is an important therapeutic method for the treatment of NSCLC, however, with the overall efficiency rate of only 20–40%. With the rapid development of molecular biology in recent years, the interference of ERCC1 expression has been shown to be able to enhance the sensitivity of a variety of tumor cells to platinum drugs, including lung, colon, liver, and ovarian cancers ( 22 – 25 ). Olaussen et al ( 26 ) have shown that according to the immunohistochemical staining for the NSCLC patients at stages I–III after radical resection, the ERCC1-negatie patients could benefit from the platinum-based chemotherapy, while ERCC1-overexpressing patients could not.…”