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Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers

Oncogene volume 33, pages 966–976 (2014)Cite this article

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Abstract

The gene encoding the receptor tyrosine kinase ERBB2, also known as HER2, is amplified and/or overexpressed in up to 15% of breast cancers. These tumours are characterised by an aggressive phenotype and poor clinical outcome. Although therapies targeted at ERBB2 have proven effective, many patients fail to respond to treatment or become resistant and the reasons for this are still largely unknown. Using a high-throughput functional screen we assessed whether genes found to be recurrently amplified and overexpressed in ERBB2+ve breast cancers mediate resistance to the ERBB2-targeted agent lapatinib. Lapatinib-resistant ERBB2-amplified breast cancer cell lines were screened, in the presence or absence of lapatinib, with an RNA interference library targeting 369 genes recurrently amplified and overexpressed in both ERBB2-amplified breast cancer tumours and cell lines. Small interfering RNAs targeting a number of genes caused sensitivity to lapatinib in this context. The mechanisms of resistance conferred by the identified genes were further investigated and in the case of NIBP (TRAPPC9), lapatinib resistance was found to be mediated through NF-κB signalling. Our results indicate that specific amplified and/ or overexpressed genes found in ERBB2-amplified breast cancer may mediate response to ERBB2-targeting agents.

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Acknowledgements

We thank Breakthrough Breast Cancer and AACR SU2C for funding this work. We acknowledge NHS funding to the NIHR RMH Biomedical research Centre. We thank Dr David Watkins from the Royal Marsden hospital for the kind donation of the CR-OE33 cell line.

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, UK, London

    D Wetterskog, K-K Shiu, I Chong, T Meijer, A Mackay, M Lambros, J S Reis-Filho, C J Lord & A Ashworth

  2. GI Unit, Royal Marsden Hospital, Sutton, UK

    I Chong & D Cunningham

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  1. D Wetterskog
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  2. K-K Shiu
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Correspondence to J S Reis-Filho, C J Lord or A Ashworth.

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Wetterskog, D., Shiu, KK., Chong, I. et al. Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers. Oncogene 33, 966–976 (2014). https://doi.org/10.1038/onc.2013.41

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