A Single Nucleotide Polymorphism in SLC7A5 Was Associated With Clinical Response in Multiple Myeloma Patients

Abstract

Background/Aim: SLC7A5 is recognized as the major mediator of melphalan uptake into multiple myeloma (MM) cells; however, its contribution to the inter-patient variability of melphalan efficacy and toxicity is yet to be well elucidated. This study aimed to investigate the impact of a single nucleotide polymorphism (SNP) rs4240803 in SLC7A5 on the gene expression, ex vivo sensitivity to melphalan, and clinical outcomes in MM patients who were undergoing autologous stem cell transplantation with high-dose melphalan. Materials and Methods: Peripheral blood mononuclear cells (PBMC) were collected from 108 MM patients prior to melphalan therapy. Clinical data were also collected from these patients following melphalan therapy. Results: rs4240803 was associated with elevated expression of SLC7A5 mRNA, higher ex vivo sensitivity to melphalan in PBMCs, and positive 90-day response in these patients (p=0.047, 0.10, 0.049, respectively). Conclusion: rs4240803 impacted the expression of SLC7A5, thus contributing to the clinical response of MM patients to melphalan therapy.

Influence of single nucleotide polymorphism of LAT1 on therapeutic response to gabapentinoids in Pakistani patients with neuropathic pain

“…Results of our study are consistent with previous studies suggesting the role of elevated expression of SLC7A5 rs4240803 in enhanced uptake of melphalan into tumour cells and subsequent better clinical outcomes of melphalan in multiple myeloma patients 13 . LAT1 rs4240803 SNP was also found to have a significant effect on gastrointestinal toxicity in the form of oral mucositis and neutropenia and variable plasma concentrations of melphalan in multiple myeloma patients 12,27 .…”

“…As LAT1 is an important transporter of gabapentinoids across BBB, patients with G/A variant of LAT1 could have altered expression of LAT1 in apical and basolateral membrane of the BBB, contributing to altered clinical outcomes in the form of partial response or no response at all to gabapentinoids. Given the location of rs4240803 within the first intron of SLC7A5 in the proximity of a putative transcription enhancer, altered SLC7A5 protein expression might affect the behaviour of drugs substrate for LAT1 12,13 …”

“…Pharmacogenetic studies have documented SLC7A5 upregulated expression in different tumour growth and progression and association of a single nucleotide polymorphism G/A of rs4240803 in the first intron of SLC7A5 with altered mRNA expression due to its location near a putative transcriptional enhancer 11 . Overexpression of rs4240803 has been suggested to be involved in gastrointestinal toxicity with melphalan and in positive 90‐day response and progression‐free survival in patients with multiple myeloma 12,13 …”

Development of a method for clinical pharmacokinetic testing to allow for targeted Melphalan dosing in multiple myeloma patients undergoing autologous transplant

“…Melphalan is a DNA‐alkylator that is highly bound to red cell membrane proteins and undergoes ~40% renal elimination 9,13–16,36 . In addition, a single nucleotide polymorphism (rs4240803) in SLC7A5, a gene that encodes L‐type amino acid transporter 1 (LAT1), which is a transporter that mediates melphalan uptake into cells, has been associated with increased mucositis and requirement for total parenteral nutrition but also has been linked to response 10,31,32,37 . Factors modifying melphalan exposure could explain recent studies that suggest that HDM PK significantly impacts ASCT outcomes 15–18 .…”

“…9,[13][14][15][16]36 In addition, a single nucleotide polymorphism (rs4240803) in SLC7A5, a gene that encodes L-type amino acid transporter 1 (LAT1), which is a transporter that mediates melphalan uptake into cells, has been associated with increased mucositis and requirement for total parenteral nutrition but also has been linked to response. 10,31,32,37 Factors modifying melphalan exposure could explain recent studies that suggest that HDM PK significantly impacts ASCT outcomes. [15][16][17][18] Several groups have demonstrated that a higher HDM AUC leads to improved overall survival and increased toxicities (e.g.…”