EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D3 in acute myeloid leukemia cells.

Abstract

By means of an unbiased, automated fluorescence microscopy-based screen, we identified the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib as potent enhancers of the differentiation of HL-60 acute myeloid leukemia (AML) cells exposed to suboptimal concentrations of vitamin A (all-trans retinoic acid, ATRA) or vitamin D (1α,25-hydroxycholecalciferol, VD). Erlotinib and gefitinib alone did not promote differentiation, yet stimulated the acquisition of morphological and biochemical maturation markers (including the expression of CD11b and CD14 as well as increased NADPH oxidase activity) when combined with either ATRA or VD. Moreover, the combination of erlotinib and ATRA or VD synergistically induced all the processes that are normally linked to terminal hematopoietic differentiation, namely, a delayed proliferation arrest in the G0/G1 phase of the cell cycle, cellular senescence, and apoptosis. Erlotinib potently inhibited the (auto)phosphorylation of mitogen-activated protein kinase 14 (MAPK14, best known as p38(MAPK)) and SRC family kinases (SFKs). If combined with the administration of ATRA or VD, the inhibition of p38(MAPK) or SFKs with specific pharmacological agents mimicked the pro-differentiation activity of erlotinib. These data were obtained with 2 distinct AML cell lines (HL-60 and MOLM-13 cells) and could be confirmed on primary leukemic blasts isolated from the circulation of AML patients. Altogether, these findings point to a new regimen for the treatment of AML, in which naturally occurring pro-differentiation agents (ATRA or VD) may be combined with EGFR inhibitors.

• Authors: Elodie Lainey, Alice Wolfromm, Abdul Qader Sukkurwala, Jean-Baptiste Micol, Pierre Fenaux, Lorenzo Galluzzi, Oliver Kepp, Guido Kroemer
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 12 Issue 18 Pg. 2978-91 (Sep 15 2013) ISSN: 1551-4005 [Electronic] United States
• PMID: 23974111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD34
• CD11b Antigen
• Protein Kinase Inhibitors
• Quinazolines
• Cholecalciferol
• Tretinoin
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• src-Family Kinases
• Mitogen-Activated Protein Kinase 14

Topics

• Antigens, CD34 (metabolism)
• CD11b Antigen (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Cholecalciferol (pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (metabolism, pathology)
• Mitogen-Activated Protein Kinase 14 (metabolism)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Tretinoin (pharmacology)
• Tumor Cells, Cultured
• src-Family Kinases (metabolism)