Inhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma

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.

Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno‐foetal amino acid transport

“…JPH203 was previously reported as potent, LAT1-specific inhibitor. [27][28][29][30][31]46 JX009 had been described in the patent literature 37 to inhibit LAT1-mediated transport with similar efficacy as JPH203, albeit with significantly lower specificity, that is, it is also a potent LAT2 inhibitor. As no other LAT2 inhibitors have been described in the literature, JX009 was considered the best available tool for the assessment of LAT2-related transport of leucine.…”

“…Due to the varying SLC7 specificity, different inhibition patterns were expected. JPH203 was previously reported as potent, LAT1‐specific inhibitor 27‐31,46 . JX009 had been described in the patent literature 37 to inhibit LAT1‐mediated transport with similar efficacy as JPH203, albeit with significantly lower specificity, that is, it is also a potent LAT2 inhibitor.…”

“…Since LAT1 was found to be selectively expressed and up‐regulated in various rapidly proliferative cancer types 18‐20 and has a putative role in drug delivery across the blood‐brain barrier, 21 efforts have been made to pharmaceutically target this transporter using substrate‐mimicking or virtual screening approaches 22‐26 . The substrate‐mimicking tyrosine analog JPH203 (also known as KYT‐0353) was tested in several in vitro and in vivo cancer cell proliferation experiments and described as potent LAT1‐specific inhibitor 27‐31 . To delineate the contribution of LAT1 from LAT2 in materno‐foetal leucine transport, we synthesized the LAT1‐specific inhibitor JPH203, the structurally closely related inhibitor (JG336), as well as a third small molecule inhibitor (JX009) with comparable leucine uptake inhibition efficiency but lower LAT1‐specificity (structures see Figure 4).…”

“…[22][23][24][25][26] The substrate-mimicking tyrosine analog JPH203 (also known as was tested in several in vitro and in vivo cancer cell proliferation experiments and described as potent LAT1-specific inhibitor. [27][28][29][30][31] To delineate the contribution of LAT1 from LAT2 in materno-foetal leucine transport, we synthesized the LAT1-specific inhibitor JPH203, the structurally closely related inhibitor (JG336), as well as a third small molecule inhibitor (JX009) with comparable leucine uptake inhibition efficiency but lower LAT1-specificity (structures see Figure 4).…”

The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

“…JPH203 is a tyrosine analogue that was designed based on the structure of the thyroid hormone triiodothyronine (T3), which is a substrate of LAT1 and LAT2 [108,109]. JPH203 was subsequently tested in other cancer types and successfully reduced growth of brain [71], gastric [80], head and neck [86], leukemia [50], lung [78], kidney [78], prostate [95], thymic carcinoma [96], and thyroid cancer [59] cell lines. Importantly, LAT1 inhibition by JPH203 has demonstrated a convincing potential in vivo as shown by a diminished tumor growth in xenograft models of human leukemia cells [50] and colon cancer cells [79].…”