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Annals of Oncology Advance Access published online on July 24, 2009
Annals of Oncology, doi:10.1093/annonc/mdp304
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines

Y. Kataoka1, T. Mukohara2,3,*, H. Shimada4, N. Saijo4, M. Hirai1 and H. Minami2,3

1 Hospital Pharmacy
2 Cancer Center, Kobe University Hospital
3 Medical Oncology, Department of Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe
4 Research Center for Innovative Oncology, National Cancer Hospital East, Kashiwa, Japan

* Correspondence to: Dr T. Mukohara, Department of Medical Oncology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel: +81-78-382-5825; Fax: +81-78-382-5821; E-mail: mukohara{at}med.kobe-u.ac.jp

Background: The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells.

Materials and methods: We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR).

Results: Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 µg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 µM CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype.

Conclusions: PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.

breast cancer, HER2, PIK3CA, trastuzumab

Received for publication April 24, 2009. Accepted for publication May 4, 2009.


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