Abstract
Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo‐ and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L‐type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1‐specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD‐MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long‐term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.
Highlights
Medulloblastoma (MB) is the most prevalent pediatric brain tumour.[1]
We subsequently show that JPH203 treatment disrupts amino acid (AA) homeostasis, mTORC1 activity as well as proliferation and survival of both MB cell lines
JPH203 still displayed strong anti‐proliferative and cytotoxic effects on both cell lines (Figure 4B,C). These results strongly suggest that this 4‐month adaptation was insufficient to induce resistance to L‐type amino acid transporter 1 (LAT1) inhibition the chronic treatment with JPH203 led to up‐regulation of some components of the amino acid transport machinery
Summary
Medulloblastoma (MB) is the most prevalent pediatric brain tumour.[1]. Recent advances in genetic characterization of the disease have led to an international consensus classification of MB into four biologically and clinically relevant subtypes: the wingless (Wnt), the sonic hedgehog (Shh) and the more similar though molecularly distinguishable groups 3 and 4.2,3 The most recent studies combining genetics, epigenetics and RNA expression data have refined and further delineated several subgroups within these groups.[3-6]. Clinical trials involving Shh pathway targeted inhibitors have enrolled Shh group MB patients based on this assertion To date, these trials have not led to the expected results as they have induced unbearable toxicity and tumour resistance to the treatment.[13-15]. Essential amino acids (EAAs), which cannot be synthetized de novo by human cells, are absolutely required for cancer cell proliferation. Some of these nutrients can be converted to essential metabolite intermediates of the TCA cycle, further participating in tumour energy metabolism and macromolecule synthesis. We demonstrate that LAT1 is the main leucine transporter in two independent cell lines isolated from Shh (DAOY) and Group 3 (HD‐MB03) MBs.[27,28]. Our in vitro results strongly suggest that JPH203 is a promising therapeutic candidate for treating MB
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