Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells

Vivian Wai Yan Lui, Cecilia Pik Yuk Lau, Ka Kiu Ho, Margaret Heung Ling Ng, Suk Hang Cheng, Sai Wah Tsao, Chi Man Tsang, Kenny Ieng Kit Lei, Anthony T.C. Chan, Tony Shu Kam Mok

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit antitumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC 50∼600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G 0/G 1 cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities.

Original languageEnglish (US)
Pages (from-to)1241-1252
Number of pages12
JournalInvestigational New Drugs
Volume29
Issue number6
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Anoikis-sensitization
  • Anti-invasion
  • Lapatinib
  • NPC

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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