Pneumologie 2015; 69 - A70
DOI: 10.1055/s-0035-1556662

Impact of epidermal growth factor receptor (EGFR) inhibitors on cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines in parallel to naïve cells at therapeutic doses

V Pamidiboina 1, F Tian 1, K Rosemarie 1, M Schaule 1, RM Huber 1
  • 1Division of Respiratory Medicine and Thoracic Oncology, Medizinische Klinik V, LMU, and Thoracic Oncology Centre Munich, Germany

Introduction: Chemotherapy represents the backbone of treatment of advanced NSCLC; a platinum-based doublet is standard in first-line treatment. But resistance limits the effectiveness of anticancer drugs and is the major cause of relapse and cancer mortality. Cisplatin activates membrane-integrated proteins, like the EGFR. As in more than 60% of NSCLC s EGFR is overexpressed and in about 10% activated by a driver mutation, EGFR is a further target. We tested whether EGFR TKIs influence cisplatin resistance (CR).

Methods: For the experiments H838 (wild type EGFR), HCC827 (delE746-A750) and H1975 (L858R, T790 M) cell lines were used. Naïve and CR cells were treated with clinically used concentrations (human dose of plasma Cmax): cisplatin 1 µg/ml, erlotinib-4.7µM, gefitinib-0.4µM, afatinib-62nM, rociletinib-360nM. Subsequently cell growth curves and cell proliferation was calculated by trypan blue exclusion cell counting, cell titer blue reagent assay and apoptosis (Annexin V/PI staining) by means of flow cytometry.

Results: We found that after cisplatin 1-µg/ml CR cells retain their resistance irrespective of EGFR mutational status. Erlotinib potentiates growth inhibition of H838 CR cells. CR didn't affect the EGFR inhibitor efficacy in HCC827 CR cells. Afatinib and rociletinib showed cell growth inhibition after 48h of treatment in H1975 CR phenotype. HCC827 CR cells showed more apoptosis after 24h of treatment. EGFR inhibitors didn't affect the H838 CR phenotype and H1975 CR cells expressed high apoptotic population with gefitinib and afatinib. Cisplatin IC50 was increased marginally in H838 and H1975 CR phenotype. Gefitinib IC50 was significantly reduced in H838 CR cells and Erlotinib IC50 was significantly increased in H1975 CR cells.

Conclusions: There are differences between Gefitinib and the 2 nd/3 rd generation inhibitors in naïve and cisplatin resistant cell lines depending on the genetic status of EGFR. Combinations may be relevant for clinical use.

*Presenting author