Abstract
Lapatinib promotes induction of c-MYC, resulting in reduced lapatinib sensitivity in HER2+ cells.
Major finding: Lapatinib promotes induction of c-MYC, resulting in reduced lapatinib sensitivity in HER2+ cells.
Mechanism: Lapatinib activates FOXOs, leading to a MLL2/BRD4–dependent increase in c-MYC expression.
Impact: Inhibition of the MLL2/FOXO/BRD4/c-MYC axis may reduce resistance of HER2+ tumors to HER2 inhibitors.
HER2 (ERBB2) is commonly overexpressed in breast cancer and associated with poor prognosis. HER2-targeted therapies are available for the treatment of HER2+ breast cancer, including the tyrosine kinase inhibitor lapatinib; however, cancer cells often develop resistance to lapatinib treatment. Lapatinib resistance is associated with increased estrogen receptor signaling and upregulation of prosurvival factors and receptor tyrosine kinases, but the epigenetic mechanisms controlling lapatinib resistance are not well understood. Matkar and colleagues characterized an epigenetic mechanism by which lapatinib promotes c-MYC expression and reduced sensitivity to lapatinib. An shRNA screen identified the mixed lineage leukemia 2 (MLL2) protein, a histone methyltransferase involved in activating gene transcription, as an essential regulator of HER2+ breast cancer cell growth. Lapatinib treatment and MLL2 induced expression of c-MYC, which was required to reduce the sensitivity of HER2+ breast cancer cells to lapatinib. Mechanistically, lapatinib-induced upregulation of c-MYC was mediated by activation of FOXO transcription factors following suppression of the HER2–PI3K–AKT pathway. Lapatinib promoted direct binding of FOXO1/3 to the MYC promoter and recruitment of MLL2 to the promoter, which resulted in an increase in activating histone marks and activation of HER2 gene transcription. Bromodomain-containing 4 (BRD4), another epigenetic regulator, was also bound to the MYC promoter in lapatinib-treated cells, further supporting the role of epigenetic regulation in regulating sensitivity to HER2 inhibitors. BRD4 inhibition with a BET inhibitor synergized with lapatinib to suppress c-MYC expression and inhibit HER2+ breast cancer cell growth both in vitro and in vivo. Taken together, these findings highlight a paradoxical role for the FOXO transcription factors, which normally function as tumor suppressors, in upregulating c-MYC; provide an epigenetic mechanism for the occurrence of HER2 inhibitor resistance; and suggest that inhibiting the MLL2/FOXO/BRD4/c-MYC axis might increase the sensitivity of HER2+ breast cancer cells to lapatinib.
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