The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

Melissa J LaBonte, Philipp C Manegold, Peter M Wilson, Will Fazzone, Stan G Louie, Heinz-Josef Lenz, Robert D Ladner, Melissa LaBonte Wilson

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas.

Original languageEnglish
Pages (from-to)2957-69
Number of pages13
JournalInternational journal of cancer. Journal international du cancer
Volume125
Issue number12
DOIs
Publication statusPublished - 15 Dec 2009

Bibliographical note

Copyright (c) 2009 UICC.

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Blotting, Western
  • Camptothecin
  • Cell Cycle
  • Cell Proliferation
  • Chromatography, Liquid
  • Colonic Neoplasms
  • Colony-Forming Units Assay
  • Drug Synergism
  • Flow Cytometry
  • Humans
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Inbred BALB C
  • Quinazolines
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-2
  • Stomach Neoplasms
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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