Scientific publications

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin

Nov 9, 2022 | Magazine: Frontiers in Pharmacology

Evelien G E Hurkmans  1 , Jan B Koenderink  2 , Jeroen J M W van den Heuvel  2 , Yvonne M H Versleijen-Jonkers  3 , Melissa H S Hillebrandt-Roeffen  3 , Johanne M Groothuismink  1 , Hanneke I Vos  1 , Winette T A van der Graaf  3   4 , Uta Flucke  5 , Grigor Muradjan  2 , Hendrik W B Schreuder  6 , Melanie M Hagleitner  7 , Han G Brunner  1 , Hans Gelderblom  8 , Anne-Marie Cleton-Jansen  9 , Henk-Jan Guchelaar  10 , Eveline S J M de Bont  11 , Daan J Touw  12 , G Jan Nijhoff  12 , Leontien C M Kremer  13 , Huib Caron  13 , Rachael Windsor  14 , Ana Patiño-García  15 , Anna González-Neira  16 , Federica Saletta  17 , Geoff McCowage  18 , Sumanth Nagabushan  18   19 , Daniel Catchpoole  17 , D Maroeska W M Te Loo  20 , Marieke J H Coenen  1

Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile.

Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002).

The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001).

Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.).

Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.

CITA DEL ARTÍCULO Front Pharmacol. 2022 Nov 9;13:1042989. doi: 10.3389/fphar.2022.1042989. eCollection 2022

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