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

Nat Commun. 2024 Jun 21;15(1):5292. doi: 10.1038/s41467-024-49667-2.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Axl Receptor Tyrosine Kinase
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins* / metabolism
  • Janus Kinase 1* / antagonists & inhibitors
  • Janus Kinase 1* / genetics
  • Janus Kinase 1* / metabolism
  • Mice
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases* / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases* / genetics
  • Receptor Protein-Tyrosine Kinases* / metabolism
  • STAT6 Transcription Factor
  • Sarcoma, Ewing* / drug therapy
  • Sarcoma, Ewing* / genetics
  • Sarcoma, Ewing* / metabolism
  • Sarcoma, Ewing* / pathology
  • Signal Transduction* / drug effects
  • Xenograft Model Antitumor Assays
  • c-Mer Tyrosine Kinase / genetics
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • Janus Kinase 1
  • JAK1 protein, human
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • Intercellular Signaling Peptides and Proteins
  • Axl Receptor Tyrosine Kinase
  • STAT6 protein, human
  • Proto-Oncogene Proteins
  • AXL protein, human
  • c-Mer Tyrosine Kinase
  • MERTK protein, human
  • TYRO3 protein, human
  • Antineoplastic Agents
  • STAT6 Transcription Factor