Pharmacogenetics of ABCG2 and adverse reactions to gefitinib

George Cusatis, Vanesa Gregorc, Jing Li, Anna Spreafico, Roxann G. Ingersoll, Jaap Verweij, Vienna Ludovini, Eugenio Villa, Manuel Hidalgo, Alex Sparreboom, Sharyn D. Baker

Research output: Contribution to journalArticlepeer-review

203 Scopus citations


Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non-small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug-induced diarrhea, with implications for optimizing treatment with such agents.

Original languageEnglish (US)
Pages (from-to)1739-1742
Number of pages4
JournalJournal of the National Cancer Institute
Issue number23
StatePublished - Dec 6 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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