Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

Koichi Azuma, Junji Tsurutani, Kazuko Sakai, Hiroyasu Kaneda, Yasuhito Fujisaka, Masayuki Takeda, Masahiro Watatani, Tokuzo Arao, Taroh Satoh, Isamu Okamoto, Takayasu Kurata, Kazuto Nishio, Kazuhiko Nakagawa

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Abstract

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 FGFR2 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 FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

Original languageEnglish
Pages (from-to)219-224
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume407
Issue number1
DOIs
Publication statusPublished - Apr 1 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Azuma, K., Tsurutani, J., Sakai, K., Kaneda, H., Fujisaka, Y., Takeda, M., Watatani, M., Arao, T., Satoh, T., Okamoto, I., Kurata, T., Nishio, K., & Nakagawa, K. (2011). Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure. Biochemical and Biophysical Research Communications, 407(1), 219-224. https://doi.org/10.1016/j.bbrc.2011.03.002