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The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration in vitro and exerted significant antitumor activity in vivo . AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.

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ABSTRACT. L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors, in contrast to its limited distribution and low-level expression in normal tissues. In this study, to explore the feasibility of using LAT1 expression as a molecular marker in mammary gland tumors (MGT), we performed a comparative study of LAT1 expression at the mRNA and protein levels in normal mammary gland cells and tumor cells. Conventional RT-PCR and Western blotting were performed on MGT tissues from 16 dogs and normal organs from nine healthy dogs. LAT1 expression was detected in ten of the 16 MGT patients. As is the case in human tissues, LAT1 showed limited expressional distribution in normal canine organs. For quantitative expressional comparison, extensive real-time RT-PCR was performed on mRNA samples from 53 MGT patients. The comparison demonstrated that LAT1 mRNA levels from MGT tissues were 20 times higher than those in normal mammary gland tissues. Additionally, histologically invasive MGT showed a higher expression of LAT1 than non-invasive tumors. These findings suggest that LAT1 could be a clinical marker and therapeutic target for invasive malignant MGT. Amino acid transport system L, including basolateral amino acid transporters, transports branched or aromatic amino acids such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine and histidine into cells in a Na-independent manner [9,21,26]. The system is essential for fundamental cellular activities such as cellular growth, proliferation and maintenance because of its role in providing the amino acids necessary for the cellular activities [4,13]. L-type amino acid transporter 1 (LAT1), one of four molecular correlates of system L, has recently received a lot of attention owing to observations that many tumor cell lines and primary human tumors highly and preferentially express LAT1, in contrast to its limited distribution and low-level expression in normal tissues [10,13,17,23,26].The functional significance of LAT1 expression in tumor cells has been investigated in a variety of human tumor tissues and animal models. In a rat colon cancer model, the demonstration that tumors positive for LAT1 expression were larger than negative tumors suggests that LAT1 is a predictive marker for tumor growth [7]. Additionally, a significant role in metastatic processes has been proposed based on accumulated evidence, including up-regulated expression of LAT1 in metastasized tumor tissues and a high incidence of metastasis in tumors with up-regulated expression of LAT1 [7,17]. For functional expression of LAT1 in tumor cells, a covalent association with a protein, the heavy chain of the 4F2 cell surface antigen (CD98), in plasma membrane has been dem...

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