Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'afatinib éradique les cellules souches cancéreuses et suggère l'intérêt de cette thérapie ciblée, en combinaison avec le topotecan, pour le traitement des cancers
Cancer stem-like cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ABCG2 confers chemoresistance to CSC where it serves as a potential biomarker and therapeutic target. Here we show that afatinib, a small molecule inhibitor of the tyrosine kinases EGFR, HER-2 and HER-4, preferentially eliminated side population (SP) cells with CSC character, in both cell lines or patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication.