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EGFR and HER2 inhibition in pancreatic cancer

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Summary

The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC50 < 2 μM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5’deoxy-5’fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.

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Acknowledgments

This work was supported by funding from Ireland’s Higher Educational Authority Programme for Research in Third Level Institutions (PRTLI) Cycle 3 and 4, and the Cancer Clinical Research Trust, Ireland.

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The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland

    Naomi Walsh, AnneMarie Larkin, Brendan Corkery, Martin Clynes, John Crown & Norma O’Donovan

  2. St. Vincent’s University Hospital, Dublin, Ireland

    Susan Kennedy, Brendan Corkery & John Crown

  3. Molecular Therapeutics for Cancer Ireland, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland

    Lorraine O’Driscoll

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  1. Naomi Walsh
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  2. Susan Kennedy
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Correspondence to Naomi Walsh.

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Fig S1

HER2 (A) and EGFR (B) expression levels as measured by ELISA (pg/μl of total protein). (TIFF 60 kb)

Fig. S2

Fixed combination proliferation assays of pancreatic cancer cell lines, BxPc-3 and HPAC treated with lapatinib in combination with chemotherapeutic drugs gemcitabine and 5dFUrd. Fixed concentration ratio of lapatinib to gemcitabine (1:0.01) and lapatinib to 5’dFUrd (1:8). (TIFF 87 kb)

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Walsh, N., Kennedy, S., Larkin, A. et al. EGFR and HER2 inhibition in pancreatic cancer. Invest New Drugs 31, 558–566 (2013). https://doi.org/10.1007/s10637-012-9891-x

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