Erlotinib antagonizes ABC transporters in acute myeloid leukemia

• DOI: 10.4161/cc.22382
• Publication Date: 2012-10-22T21:06:38Z
• Authors: Elodie Lainey; Marie Sébert; Sylvain Thépot; Marie Scoazec; Cyrielle Bouteloup; Carole Leroy; Stéphane De Botton; Lorenzo Galluzzi; Pierre Fenaux; Guido Kroemer
• Keywords: EGFR Inhibitors; Abcg2

Erlotinib was originally developed as an epidermal growth factor receptor (EGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and vivo. The molecular mechanisms underlying clinical activity erlotinib a standalone agent have not been precisely elucidated. Conversely, preclinical settings, has shown to inhibit constitutive activation SRC kinases mTOR, well synergize with DNA methyltransferase azacytidine (a reference therapeutic subset leukemia patients) by promoting its intracellular accumulation. Here, we show that both gefitinib (another EGFR inhibitor) transmembrane transporters ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) breast cancer resistance protein (BCRP), acute myeloid (AML) cells do overexpress these pumps. Thus, inhibition drug efflux selectively exacerbated (in synergistic or additive fashion) cytotoxic response KG-1 chemotherapeutic agents are normally extruded ABC (e.g., doxorubicin etoposide). limited export via multiple mechanisms, downregulation surface-exposed pumps modulation their ATPase activity. on chemosensitization profile persisted patient-derived CD34+ cells, suggesting might be particularly efficient antagonizing leukemic (stem cell) subpopulations, irrespective whether they exhibit increased transporters.