Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma

• Published in: Nature communications Vol. 15; no. 1; pp. 5292 - 19
• Main Authors: Yu, Le, Deng, Yu, Wang, Xiaodong, Santos, Charlene, Davis, Ian J., Earp, H. Shelton, Liu, Pengda
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/44; 13/51; 13/95; 14/19; 14/63; 38/22; 38/70; 38/77; 631/67/1059; 631/67/1798; 631/67/2332; 64/60; 82/83; AKT protein; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Autocrine signalling; Axl protein; Axl Receptor Tyrosine Kinase; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Bone surgery; c-Mer Tyrosine Kinase - genetics; c-Mer Tyrosine Kinase - metabolism; Cell Line, Tumor; Chemoresistance; Chemotherapy; Clinical trials; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Effectiveness; Ewing's sarcoma; Ewings sarcoma; Female; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Janus kinase; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Kinases; Mice; multidisciplinary; Nuclear transport; Paracrine signalling; Patients; Pediatrics; Phosphorylation; Phosphorylation - drug effects; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Quality of life; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Sarcoma; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - genetics; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - pathology; Science; Science (multidisciplinary); Signal Transduction - drug effects; Soft tissues; Solid tumors; Stat6 protein; STAT6 Transcription Factor; Translocation; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49667-2

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value. Due to limited therapeutic options, patients with Ewing sarcoma typically receive intensive chemotherapy which limits quality of life and often resistance develops. Here, the authors identify a chemotherapy-induced JAK-STAT-GAS6-TAM kinase signaling cascade in Ewing sarcoma and therapeutically target this axis with TAM kinase inhibition.