Corresponding Author: Daniel Hochhauser, UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London WC1E 6BT, UK.
Mol Cancer Ther. 2013 Dec;12(12):2897-908. doi: 10.1158/1535-7163.MCT-12-1049. Epub 2013 Oct 3.
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.
表皮生长因子受体（EGFR）在包括肺癌、结直肠癌和乳腺癌在内的实体瘤中可被抗体和小分子药物靶向治疗。然而，化疗仍然很重要，通过与靶向药物联合来提高疗效的努力具有挑战性。本研究检测了短时间和长时间暴露于 EGFR 和 HER2 靶向酪氨酸激酶抑制剂（TKI）吉非替尼和拉帕替尼对拓扑异构酶 IIα（Topo IIα）毒物诱导的 SK-Br-3 人表皮生长因子受体 2（HER2）扩增乳腺癌细胞系细胞死亡和 DNA 损伤的影响。短时间（1 小时）暴露于吉非替尼或拉帕替尼均不会影响 Topo IIα 毒物阿霉素、依托泊苷和 m-AMSA 诱导的细胞凋亡。相比之下，用这三种药物处理 48 小时的细胞则具有耐药性。短时间（1 小时）暴露于 TKI 不会改变诱导的 DNA 单链或双链断裂（DSB）的数量，而较长时间（48 小时）暴露则会减少 DNA DSB 的数量和 γ-H2AX 焦点的形成。吉非替尼和拉帕替尼在 48 小时均降低了 Topo IIα 的表达和活性。使用可诱导下调 Topo IIα 的细胞系进行的研究表明，Topo IIα 的表达而非 Topo IIβ 的表达决定了这些化疗药物诱导的 DNA 链断裂的数量。这些结果表明，EGFR 和 HER2 靶向 TKI 的长时间暴露通过下调 Topo IIα 诱导对阿霉素、依托泊苷和 m-AMSA 的耐药性。这可能解释了为什么它们添加到化疗方案中并未增加疗效。
