Abstract
The EGF receptor (EGFR) is therapeutically targeted by antibodies and small molecules in solid tumors including lung, colorectal, and breast cancer. However, chemotherapy remains important, and efforts to improve efficacy through combination with targeted agents is challenging. This study examined the effects of short and long durations of exposure to the EGFR- and HER2-targeted tyrosine kinase inhibitors (TKI) gefitinib and lapatinib, on induction of cell death and DNA damage by topoisomerase IIα (Topo IIα) poisons, in the SK-Br-3 HER2-amplified breast cancer cell line. Short exposure to either gefitinib or lapatinib for 1 hour did not affect the induction of apoptosis by the Topo IIα poisons doxorubicin, etoposide, and m-AMSA. In contrast, cells treated for 48 hours were resistant to all three drugs. Short exposure (1 hour) to TKI did not alter the number of DNA single- or double-strand breaks (DSB) induced, whereas longer exposure (48 hours) reduced the number of DNA DSBs and the formation of γ-H2AX foci. Both gefitinib and lapatinib reduced the expression and activity of Topo IIα at 48 hours. Studies using a cell line with inducible downregulation of Topo IIα showed that expression of Topo IIα, and not Topo IIβ, determined the number of DNA strand breaks induced by these chemotherapeutic agents. These results indicate that prolonged exposure to TKIs targeting EGFR and HER2 induce resistance to doxorubicin, etoposide, and m-AMSA through downregulation of Topo IIα. This may explain why their addition to chemotherapy regimens have not increased efficacy.
Highlights
The development of targeted therapies marked a major advance in the systemic treatment of cancer
Treatment with gefitinib (5 mmol/L) inhibits EGF receptor (EGFR), HER2, and HER3 signaling within 1 hour but with continued exposure, HER3 signaling is reactivated by 48 hours [13]
These results indicate that gefitinib treatment for 48 hours renders cells resistant to the cytotoxic effects of doxorubicin, m-AMSA, and etoposide
Summary
The development of targeted therapies marked a major advance in the systemic treatment of cancer. Despite their success, these agents are only useful in the management of a minority of patients and cytotoxic chemotherapy remains an important treatment modality in the management of solid tumors including lung, gastric, breast, and colorectal cancers. Several drugs target members of the human EGF receptor (EGFR/HER) family This family comprises 4 membrane receptors, EGFR (HER1/erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4) and they activate key cell signaling pathways controlling cell growth, proliferation, migration, apoptosis, and resistance to cytotoxic agents [1]. EGFR mediates resistance to DNA-damaging agents, including irradiation (IR) and cisplatin, through the activation of cell survival pathways and modulation of DNA protein kinase (DNA-PK; refs. 2–5), a key protein involved in the repair of DNA damage through the nonhomologous end-joining pathway
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