Abstract 2559: Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer

Abstract

Abstract Background : Lung cancer is the first cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (EGFR-TKI) have improved the survival of patient harboring EGFR activating mutations. Besides, EGFR-TKIs have shown clinical activity for patients with wild type EGFR (wtEGFR) tumors as maintenance treatment and for a fraction of them as second line treatment. These observations impel us to objective and document the mechanisms implicated in order to optimize the use of EGFR-TKI in the treatment of wtEGFR lung cancer. Methods : In vitro experiments rely on lung cancer cell lines expressing either wtEGFR or mutated EGFR. Their sensitivity to erlotinib in control conditions or short after a sublethal cisplatin treatment was studied. In vitro results were validated on lung patients-derived xenografts (PDX) with four wtEGFR human adenocarcinomas. Results : Cisplatin pretreatment enhances erlotinib toxicity in wtEGFR cells (providing its robust expression) but not in EGFR-mutated cells. Cisplatin priming increases erlotinib toxicity either through apoptosis or autophagy depending on the cell line. This sensitization correlates with an increase in EGFR expression and phosphorylation and a raise in AKT and Erk phosphorylation. The sensitization is also observed during long-term cisplatin treatment in a cisplatin-resistant subpopulation, together with concomitant EGFR pathway activation. The in vivo experiments conducted in PDX confirm that cisplatin pretreatment potentiates erlotinib in three of the four wtEGFR lung tumors models. Of note, the sensitization to erlotinib occured independently from KRas status. Conclusion : The sensitivity of the wtEGFR lung cancer cells and lung cancer xenografts to erlotinib is enhanced by cisplatin pretreatment, whatever the type of induced cell death. Cisplatin induces activation of EGFR and his downstream kinases AKT and Erk. This sensitization is independent from the tumor K-Ras status. EGFR phosphorylation could be a potential marker of this sensitization and might be predicitive of the optimal efficiency of EGFR TKI. In vivo validation of this marker is still ongoing. This study was supported by Roche laboratory and by the foundation for medical research. Citation Format: Judith Raimbourg, Mathilde Cabart, Marie-Pierre Joalland, Didier Decaudin, Ludmilla Deplater, Didier Lanoe, Jean-Yves Douillard, Jaafar Bennouna, François Vallette, Lisenn Lalier. Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer. [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 2559. doi:10.1158/1538-7445.AM2015-2559