Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure
Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure
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DOI：
10.1016/j.bbrc.2011.03.002
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发表时间：
2011-04-01
影响因子：
3.1
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Azuma, Koichi;Tsurutani, Junji;Nakagawa, Kazuhiko
靶向HER 2的药物改善了HER 2扩增乳腺癌患者的预后。然而，最初对这种靶向治疗有反应的患者最终会对治疗产生耐药性。我们通过将HER 2扩增和拉帕替尼敏感的UACC 812细胞长期暴露于药物，建立了拉帕替尼耐药乳腺癌细胞系（UACC 812/LR）。采用综合基因杂交技术探讨了UACC 812/LR获得拉帕替尼耐药的机制。UACC 812/LR中的FGFR 2基因高度扩增，伴随着FGER 2的过表达和HER 2的表达减少，细胞增殖试验显示，FGFR酪氨酸激酶的小分子抑制剂PD 173074在UACC 812/LR中的IC 50比在亲本细胞中低10，000倍。PD 173074降低了FGFR 2的磷酸化，并在UACC 812/LR中显著诱导凋亡，但在亲本细胞中不诱导凋亡。FGFR 2似乎是UACC 812/LR存活的关键分子，因为它们变得不依赖于HER 2途径，这表明从HER 2到FGFR 2途径的成瘾转换使癌细胞能够对HER 2靶向治疗产生抗性。目前的研究是第一个牵连FGFR在拉帕替尼耐药的发展癌症，并表明EGER靶向治疗可能成为一个有前途的补救策略拉帕替尼失败后，与HER 2阳性乳腺癌患者。(C)2011 Elsevier Inc. All rights reserved.
Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGER2 and reduced expression of HER2, and a cell proliferation assay showed that the IC50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that EGER-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer. (C) 2011 Elsevier Inc. All rights reserved.