https://phaidra.vetmeduni.ac.at/o:5393 Tyrosine kinase targeting uncovers oncogenic pathway plasticity in Tasmanian devil transmissible cancers Schönbichler, Anna Anna Schönbichler 0009-0001-5914-7782 University of Veterinary Medicine Vienna Orlova, Anna Anna Orlova 0000-0001-9262-7529 University of Veterinary Medicine Vienna Kreindl, Carmen Carmen Kreindl Endler, Lukas Lukas Endler 0000-0002-9115-8756 Wilson, Richard Richard Wilson 0000-0003-0152-4394 Kosack, Lindsay Lindsay Kosack Hofmann, Anna Anna Hofmann Viczenczova, Csilla Csilla Viczenczova Darby, Jocelyn Jocelyn Darby Erdogan, Fettah Fettah Erdogan 0000-0002-6968-4821 Patchett, Amanda L Amanda L Patchett Koren, Anna Anna Koren Kubicek, Stefan Stefan Kubicek 0000-0003-0855-8343 Müller, Mathias Mathias Müller 0000-0002-7879-3552 University of Veterinary Medicine Vienna Flies, Andrew S Andrew S Flies 0000-0002-4550-1859 Bergthaler, Andreas Andreas Bergthaler 0000-0003-0597-1976 Moriggl, Richard Richard Moriggl 0000-0003-0918-9463 University of Veterinary Medicine Vienna Springer journal article open access eng 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 DFT cancer cells exhibit distinct kinase phosphorylation profiles that dictate their responses to tyrosine kinase inhibitors. Upon long-term treatment, both DFT cell lines develop resistance, with DFT1 cells rapidly evading 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 exhibit a slowed development of resistance to imatinib, a selective kinase inhibitor with known activity against PDGFRs. Moreover, DFT2 cell 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 synergistic effects 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. Devil Facial Tumour Disease Phosphoproteomics Transmissible Cancer Tyrosine Kinase Inhibitor Resistance Combination Therapy http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:5393/download 10.1038/s44318-025-00603-0 https://phaidra.vetmeduni.ac.at/o:605 application/pdf The EMBO Journal issn:1460-2075 VoR The EMBO Journal 45 8.04 MB 2026