Erlotinib antagonizes ABC transporters in acute myeloid leukemia

Cell Cycle. 2012 Nov 1;11(21):4079-92. doi: 10.4161/cc.22382. Epub 2012 Oct 24.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD34 / metabolism
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Down-Regulation / drug effects*
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Quinazolines / therapeutic use
  • Quinazolines / toxicity*


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, CD34
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Quinazolines
  • Erlotinib Hydrochloride
  • Gefitinib