Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a “never-smoked” female patient with advanced non-small cell lung cancer

Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

“…Our current study further indicated that chronic treatment with gefitinib induced BCRP/ABCG2 expression through the Akt/nEGFR pathway, leading to the acquired gefitinib resistance. Consistent with our findings, Usuda et al (18) observed an elevated BCRP/ABCG2 expression level in a NSCLC patient with wtEGFR expression who received gefitinib therapy. Moreover, our unpublished results also indicated that blockage of BCRP/ABCG2 activity can resensitize A431/GR cells to gefitinib in vitro and potentiate the therapeutic effects of gefitinib in the A431/GR xenograft mice.…”

“…Furthermore, as mentioned above, a case report showed that a wtEGFR-expressing NSCLC patient developed acquired gefitinib resistance without any identifiable EGFR mutations. Rather, BCRP/ABCG2 expression was detected in the recurrent tumor of this patient (18). Therefore, this raises a possibility that Akt-dependent nuclear translocation of EGFR might contribute to acquired gefitinib resistance through regulation of BCRP/ABCG2 expression in wtEGFRexpressing cancer cells.…”

“…In a cell culture system with acquired resistance to gefitinib, an increased activity of insulin-like growth factor receptor by down-regulating insulin-like growth factor-binding proteins has been found to maintain the PI3K/Akt-mediated survival signaling in response to acquired gefitinib resistance in gefitinib-sensitive and wtEGFR-expressing cancer cells (16,17). In addition, it has also been reported that a non-smoking female NSCLC patient with wtEGFR expression developed acquired gefitinib resistance without any identifiable EGFR mutations (18). Further examination showed that breast cancer-resistant protein (BCRP)/ATP binding cassette subfamily G member 2 (ABCG2) was detected in this patient's recurrent tumor (18).…”

“…In addition, it has also been reported that a non-smoking female NSCLC patient with wtEGFR expression developed acquired gefitinib resistance without any identifiable EGFR mutations (18). Further examination showed that breast cancer-resistant protein (BCRP)/ATP binding cassette subfamily G member 2 (ABCG2) was detected in this patient's recurrent tumor (18). Aside for these studies, the underlying mechanisms of the sensitivity to gefitinib in wtEGFR-expressing cancer cells are still largely unknown.…”

Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

“…They reported that BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) and BCRP-transduced human non-small cell lung cancer PC-9 (PC-9/BCRP) cells have acquired cellular resistance to gefitinib. Usuda et al 69 first reported a case in which expression of BCRP was associated with acquired resistance to gefitinib. A woman who never smoked with advanced lung cancer showed acquired resistance to gefitinib without EGFR mutations.…”