Tyrosine Kinase Targeting Uncovers Oncogenic Pathway Plasticity in Tasmanian Devil Transmissible Cancers

Two transmissible cancers, Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2), have caused a significant decline in the Tasmanian devil population. DFT1 is driven by ERBB, while DFT2 is driven by PDGFRA. We show that the cancer cells exhibit distinct kinase phosphorylation profiles that dictate their responses to tyrosine kinase inhibitors. Upon long-term treatment, the cell lines develop resistance. DFT1 cells rapidly acquire resistance to ERBB inhibition without major copy number alterations or significant changes in phosphorylation, suggesting signalling plasticity and engagement of alternative oncogenic drivers. In contrast, DFT2 cells develop resistance to imatinib, a selective kinase inhibitor with known activity against PDGFRs, more slowly. Resistance is accompanied by copy number alterations and an activation of ERBB and JAK/STAT signalling with MHCI downregulation, resembling DFT1 signalling. Dual targeting of ERBB and PDGFR shows synergy in DFT1 and may prevent resistance emergence. These findings provide critical insight into the adaptive capacity of transmissible cancers and inform conservation strategies. Moreover, they highlight broader principles of kinase-driven resistance relevant to human cancers with high pathway plasticity.