Tyrosine kinase targeting uncovers oncogenic pathway plasticity in Tasmanian devil transmissible cancers

Area of Science:

• Cancer Biology
• Conservation Genetics
• Pharmacology

Background:

• Transmissible cancers Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2) threaten Tasmanian devil populations.
• DFT1 is driven by ERBB signaling, while DFT2 is driven by PDGFRA signaling.

Purpose of the Study:

• To investigate the kinase phosphorylation profiles of DFT1 and DFT2 cell lines.
• To understand the mechanisms of resistance to tyrosine kinase inhibitors.
• To inform conservation strategies for Tasmanian devils and broader cancer research.

Main Methods:

• Analysis of kinase phosphorylation profiles in DFT cell lines.
• Long-term treatment of DFT cell lines with tyrosine kinase inhibitors.
• Assessment of copy number alterations and signaling pathway activation (ERBB, JAK/STAT).

Main Results:

• DFT1 cells rapidly evade ERBB inhibition through signaling plasticity.
• DFT2 cells develop slower resistance to imatinib, involving copy number alterations and activation of ERBB and JAK/STAT pathways.
• Dual targeting of ERBB and PDGFR shows synergistic effects in DFT1 and may prevent resistance.

Conclusions:

• Transmissible cancers exhibit remarkable adaptive capacity and signaling plasticity.
• Understanding resistance mechanisms is key for developing effective therapies for DFTs and human cancers.
• Targeted therapies combined with strategies to prevent resistance are essential for conservation and treatment.