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

Le Yu, Yu Deng, Xiaodong Wang, Charlene Santos, Ian J. Davis, H. Shelton Earp and Pengda Liu ()
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Le Yu: The University of North Carolina at Chapel Hill
Yu Deng: The University of North Carolina at Chapel Hill
Xiaodong Wang: The University of North Carolina at Chapel Hill
Charlene Santos: The University of North Carolina at Chapel Hill
Ian J. Davis: The University of North Carolina at Chapel Hill
H. Shelton Earp: The University of North Carolina at Chapel Hill
Pengda Liu: The University of North Carolina at Chapel Hill

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49667-2

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