National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
Invest New Drugs. 2011 Oct;29(5):752-9. doi: 10.1007/s10637-010-9415-5. Epub 2010 Mar 16.
Overexpression of HER-2 in breast cancer is frequently associated with expression of EGFR, and EGFR expression influences response to HER-2 inhibition. The aim of this study was to examine the effects of combining dual inhibition of EGFR and HER-2, using trastuzumab, gefitinib and lapatinib, in HER-2 overexpressing breast cancer cells. Combination proliferation assays were performed in two HER-2 positive breast cancer cell lines, SKBR-3 and BT-474. Trastuzumab combined with lapatinib was also tested in BT-474 xenografts. In proliferation assays, dual targeting with trastuzumab and gefitinib or lapatinib showed synergy or additivity in both SKBR-3 and BT-474 cells. Trastuzumab (10 nM) or gefitinib (5 µM) alone did not induce significant apoptosis, whereas lapatinib (0.75 µM) induced significant apoptosis in SKBR-3 cells. Trastuzumab combined with lapatinib further enhanced apoptosis induction. Trastuzumab (10 nM) and gefitinib (5 µM) induced apoptosis comparable to lapatinib alone (0.75 µM), suggesting that inhibition of both EGFR and HER-2 may be required to induce apoptosis in these cells. Pre-treatment with trastuzumab and gefitinib or lapatinib enhanced response to chemotherapy in vitro. The combination of trastuzumab and lapatinib also effectively blocked tumour growth in vivo. Dual targeting of EGFR and HER-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.
在乳腺癌中，HER-2 的过度表达通常与 EGFR 的表达相关，而 EGFR 的表达影响 HER-2 抑制的反应。本研究的目的是研究使用曲妥珠单抗、吉非替尼和拉帕替尼双重抑制 EGFR 和 HER-2 对 HER-2 过表达乳腺癌细胞的影响。在两种 HER-2 阳性乳腺癌细胞系 SKBR-3 和 BT-474 中进行了组合增殖测定。还在 BT-474 异种移植中测试了曲妥珠单抗与拉帕替尼的联合应用。在增殖测定中，曲妥珠单抗与吉非替尼或拉帕替尼的双重靶向在 SKBR-3 和 BT-474 细胞中均表现出协同或相加作用。曲妥珠单抗（10 nM）或吉非替尼（5 µM）单独使用不会引起明显的细胞凋亡，而拉帕替尼（0.75 µM）在 SKBR-3 细胞中诱导明显的细胞凋亡。曲妥珠单抗与拉帕替尼联合进一步增强了细胞凋亡的诱导。曲妥珠单抗（10 nM）和吉非替尼（5 µM）诱导的细胞凋亡与拉帕替尼单独使用（0.75 µM）相当，表明抑制 EGFR 和 HER-2 两者可能是诱导这些细胞凋亡所必需的。曲妥珠单抗和吉非替尼或拉帕替尼预处理增强了体外化疗的反应。曲妥珠单抗和拉帕替尼的联合也有效地抑制了体内肿瘤的生长。通过将曲妥珠单抗与 EGFR/HER-2 酪氨酸激酶抑制剂联合使用，双重靶向 EGFR 和 HER-2 可能会改善同时表达 EGFR 的 HER-2 过表达乳腺癌细胞的反应。
