A SNP (rs34678167, 805 C>T, P269S) in the Human ABC Transporter ABCG2 Gene increases ABCG2-mediated Drug Resistance

ABCG2 (BCRP/MXR) is an ATP-binding cassette transporter that contributes to multidrug resistance in cancer cells by extruding a wide range of substrates, including anticancer agents. Although several non-synonymous single-nucleotide polymorphisms (SNPs) in the ABCG2 gene have been characterized, the functional consequences of many remain unclear. This study investigated the impact of SNP rs34678167 (805 C>T, P269S) on ABCG2 expression and drug resistance. Using the Flp-In™ system, we established Flp-In-293 cell lines that stably express ABCG2 (P269S) variant. Quantitative real-time PCR and Western blotting revealed that the P269S variant resulted in mRNA and protein expression levels comparable to those of WT ABCG2. Drug resistance was assessed by MTT assay using mitoxantrone and SN-38. Cells expressing ABCG2 (P269S) exhibited significantly higher EC ₅₀ values than those expressing WT ABCG2: 3.0-fold for mitoxantrone and 3.8-fold for SN-38 (p < 0.01). These results suggest that the P269S substitution enhances ABCG2-mediated drug resistance without affecting expression levels. This effect may be due to altered substrate recognition, transporter activity, or intracellular localization of the protein. Our findings underscore the importance of functionally validating genetic variants of ABCG2 and highlight the potential clinical relevance of rs34678167 in predicting drug response. This knowledge could contribute to the development of more effective therapeutic strategies tailored to the patient’s genetic background.