<scp>TYRO3</scp> , <scp>AXL</scp> , <scp>MERTK</scp> and Their Ligands in Brain Metastases From Colorectal Cancers

INTRODUCTION: TYRO3, AXL, and MERTK (TAM receptor tyrosine kinases) represent potential therapeutic targets in metastatic colorectal cancer. Pre-clinical and clinical data are needed to explore further how TAM receptors interact with the central nervous system, which could impact brain metastases from colorectal cancer (BM-CRC). METHODS: We analyzed TAM receptor expression in established brain metastasis stem cell lines from patients with CRC (BM-SC-CRC) (RNA and protein), a local cohort of BM-CRC patients (protein), and a cohort of metastatic CRC from The Cancer Genome Atlas (TCGA) (RNA). RESULTS: When orthotopically injected into mice, BM-SC-CRC derived from two patients expressed TYRO3 and Protein S (PROS1) but poorly AXL and GAS6. When we analyzed both patients' primary tumors and metastatic sites, TYRO3 and AXL proteins were expressed in all tumor sites, but hardly MERTK. AXL was located primarily in endothelial cells, and TYRO3 in tumor cells. We examined the protein expression of TAM receptors in a cohort of BM-CRC patients, considering tissue from the primary tumor (N = 85), the matched brain metastases (N = 40), and another metastatic site (N = 29). AXL was expressed through primary tumors to brain metastases, as 72.7% of samples in BM (versus 44% with TYRO3 and 53% with MERTK) had a stable (45.5%) or increased (27.2%) protein expression compared to their paired primary tumor. None of the TAM receptors or PROS1 were found prognostic in a TCGA metastatic CRC cohort (n = 80), but GAS6 was, in univariate (HR = 2.141 [95% CI 1.018-4.506], p = 0.045) and multivariate analysis (HR = 2.382 [95% CI 1.124-5.048], p = 0.024). In exploratory analysis, patients with Low AXL/High GAS6 had a poorer prognosis (p = 0.046). DISCUSSION AND CONCLUSION: The TAM receptors' ligand GAS6 and the AXL/GAS6 ratio could help to monitor patients' prognosis in metastatic CRC settings including BM-CRC. Further research is needed to validate the TAM receptors' impact on prognosis in BM-CRC.