Targeting HER2 signaling pathway for radiosensitization: Alternative strategy for therapeutic resistance

Abstract

Several studies have indicated the potential value of targeting HER-2 signaling to enhance the anti-tumor activity of ionizing radiation. However, therapeutic resistance resulting from several factors, including activation of the downstream pathway, represents a major obstacle to treatment. Here, we investigated whether inhibitors targeting downstream of HER-2 signaling would radiosensitize SKBR3 breast cancer cells that exhibit overamplification of HER2. Selective inhibition of MEK-ERK signaling using pharmacologic inhibitors (PD98059, UO126) did not increase the radiosensitivity of SKBR3 cells. Selective inhibition of the PI3K-AKT-mTOR pathway using pharmacologic inhibitors (LY294002, AKT inhibitor VIII, Rapamycin) significantly attenuated expression of p-AKT and p-70S6K, respectively and radiosensitized SKBR3 cells. MCF-7 cells those did not overexpress HER-2, showed less radiosensitization compared to SKBR3 cells by inhibition of this pathway. Pre-treatment with these inhibitors also caused significant abrogation of typical G(2) arrest following ionizing radiation and induced marked prolongation of gammaH2AX foci indicating impairment of DNA damage repair. A dual inhibitor of Class I PI3K and mTOR, PI103 effectively radiosensitized SKBR3 cells and showed significant prolongation of gammaH2AX foci. Inhibition of PI3K-AKT signaling was associated with downregulation of DNA-PKs, respectively. While apoptosis was the major mode of cell death when the cells were pretreated with LY294002 or AKT inhibitor VIII, the cells were pretreated by rapamycin or PI103 showed mixed mode of cell death including autophagy. Our results suggest possible mechanisms to counteract the HER-2 prosurvival signaling implicated in radioresistance, and offer an alternative strategy to overcome resistance to HER-2 inhibitors combined with radiation.

Targeting HER-2 Signaling Network: Implication in Radiation Response

“…We previously showed that inhibition of AKT1 using RNAi increased radiosensitivity of EGFR-or Ras-activated cell lines (Kim et al, 2005) and the other study showed that AKT inhibitor (API) or AKT1 siRNA inhibited repair of DNA double strand breaks (DSBs) in EGFR-activated lung cancer cell lines as measured by the γH2AX foci assay (Toulany et al, 2008). SKBR3 breast cancer cells having activated HER-2 signaling also showed similar findings ( Figure 3, No et al, 2009). …”

Young age is associated with ipsilateral breast tumor recurrence after breast conserving surgery and radiation therapy in patients with HER2-positive/ER-negative subtype

“…Previous research indicated that targeting of PI3K-AKT-mTOR signaling significantly radiosensitized HER2-activated breast cancer cells by inhibition of DNA repair. Therefore, blocking the PI3K-AKT-mTOR pathway may help patients to overcome resistance to currently available HER2 inhibitors plus irradiation [30].…”

“…This subtype may be relatively resistant to post-lumpectomy RT [14]. Preclinical studies have shown that EGFR expression and activation by ligands correlate with radioresistance and that signal transduction initiated by receptor activation promotes cancer cell survival and proliferation after ionizing radiation [27][28][29][30]. HER2 inhibitors can affect cellular responses to ionizing radiation by induction of apoptosis and cell cycle arrest and by impeding DNA repair [27,31].…”

Synergistic Blockade of EGFR and HER2 by New-Generation EGFR Tyrosine Kinase Inhibitor Enhances Radiation Effect in Bladder Cancer Cells

“…Toulany and colleagues (26) reported that radiation, but not EGF, enhances EGFR/HER2 heterodimerization and activates the downstream Akt signaling pathway. Given that HER2 is a prognostic factor of bladder cancer progression (27,28), some may wonder whether HER2 inhibition itself accounts for the difference in radiosensitizing activity (29,30) between afatinib and erlotinib. Our results in Fig.…”