Role of ABCA2 and its single nucleotide polymorphisms (4873T>A and 4879G>C) in the regulation of multi-drug resistance in oral squamous carcinoma cells

Lysosomal exocytosis is an essential cellular event for remodeling the extracellular matrix through secreting lysosomal enzymes and developing drug resistance. However, the detailed mechanism underlying the lysosomal exocytosis-driven acquisition of drug resistance is not completely understood. Genetic variations in gefitinib-sensitive (HSC3) and -resistant (HSC3/GR) oral squamous carcinoma cell lines were identified using whole-exome sequencing (WES). The physiological role of the ATP-binding cassette subfamily A member 2 (ABCA2) in gefitinib-induced lysosomal trafficking was evaluated in vitro, through overexpressing ABCA2 and its single nucleotide polymorphisms (SNPs). WES analysis showed that the 554 SNPs harboring 244 genes appeared to be differentially generated depending on gefitinib resistance. Among these genes, ABCA2 was enriched in 24 of 39 gene ontology terms. Two missense SNPs of ABCA2, 4873T > A (rs1831123356) and 4873T > A, were generated only in gefitinib-sensitive cells. Furthermore, HEK293 cells expressing the wild-type ABCA2 (WT ABCA2) acquired tolerance for gefitinib-induced cytotoxicity by increasing gefitinib sequestration in lysosomes and lysosomal exocytosis. Conversely, cells expressing each ABCA2 SNP exhibited lower efficacy in developing tolerance to gefitinib-induced responses than those expressing WT ABCA2. Notably, HSC3/GR cells were also tolerant to erlotinib and sunitinib but not osimertinib. Furthermore, tolerance for multiple tyrosine kinase inhibitors was attenuated by the deletion of ABCA2. These findings demonstrate that ABCA2 and its SNPs should be considered prominent targets for overcoming multi-drug resistance and enhancing the efficacy of chemotherapeutics.