Cancer Therapeutics Insights Treatment with Gefitinib or Lapatinib Induces Drug Resistance through Downregulation of Topoisomerase IIa Expression

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 longdurations of exposure to the EGFRandHER2-targeted tyrosine kinase inhibitors (TKI) gefitinib and lapatinib, on induction of cell death andDNAdamage by topoisomerase IIa (Topo IIa) poisons, in the SKBr-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 IIa 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 singleor double-strand breaks (DSB) induced, whereas longer exposure (48 hours) reduced the number of DNA DSBs and the formation of g-H2AX foci. Both gefitinib and lapatinib reduced the expression and activity of Topo IIa at 48 hours. Studies using a cell line with inducible downregulation of Topo IIa showed that expression of Topo IIa, and not Topo IIb, determined the number of DNA strand breaks induced by these chemotherapeutic agents. These results indicate that prolonged exposure to TKIs targeting EGFR andHER2 induce resistance to doxorubicin, etoposide, andm-AMSA through downregulation of Topo IIa. This may explain why their addition to chemotherapy regimens have not increased efficacy. Mol Cancer Ther; 12(12); 2897–908. 2013 AACR.