Abstract
BackgroundThe sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive.Methodology/Principal FindingsHere, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib.Conclusions/SignificanceThus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.
Highlights
The oncogenic EGFR tyrosine kinase, commonly overexpressed in a variety of solid tumors, plays important roles in cancer aetiology and progression, and is a rational target for cancer therapies
These results suggest that the induction of BCRP/ABCG2 expression may not be reversible upon the withdrawal of gefitinib and reveal that BCRP/ABCG2 expression was and irreversibly increased by gefitinib treatment, raising the possibility of the involvement of BCRP/ABCG2 in conferring acquired resistance to gefitinib
It has been reported that BCRP/ABCG2 expression can be detected in a wtEGFRexpressing patient with acquired gefitinib resistance [16]
Summary
The oncogenic EGFR tyrosine kinase, commonly overexpressed in a variety of solid tumors, plays important roles in cancer aetiology and progression, and is a rational target for cancer therapies. Selective small molecular inhibitors of EGFR tyrosine kinase (EGFR TKIs) have shown promising clinical activity in the last decade. 20–30% of NSCLC patients with amplified wild-type EGFR (wtEGFR) still demonstrated significant survival benefits from gefitinib and erlotinib treatment even though they showed lower response rate compared with patients with EGFR mutations [7,8,9]. The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive
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