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.<\/p>\n\n\n\n
Anna Sch\u00f6nbichler<\/a> <\/sup>1<\/sup><\/a>, Anna Orlova<\/a> <\/sup>1<\/sup><\/a>, Carmen Kreindl<\/a> <\/sup>1<\/sup><\/a>, Lukas Endler<\/a> <\/sup>2<\/sup><\/a>, Richard Wilson<\/a> <\/sup>3<\/sup><\/a>, Lindsay Kosack<\/a> <\/sup>4<\/sup><\/a>, Anna Hofmann<\/a> <\/sup>2<\/sup><\/a>, Csilla Viczenczova<\/a> <\/sup>2<\/sup><\/a> <\/sup>4<\/sup><\/a>, Jocelyn Darby<\/a> <\/sup>5<\/sup><\/a>, Fettah Erdogan<\/a>6<\/sup><\/a>, Amanda L Patchett<\/a> <\/sup>5<\/sup><\/a>, Anna Koren<\/a> <\/sup>4<\/sup><\/a>, Stefan Kubicek<\/a> <\/sup>4<\/sup><\/a>, Mathias M\u00fcller<\/a> <\/sup>1<\/sup><\/a>, Andrew S Flies<\/a> <\/sup>5<\/sup><\/a>, Andreas Bergthaler<\/a> <\/sup>7<\/sup><\/a> <\/sup>8<\/sup><\/a>, Richard Moriggl<\/a> <\/sup>9<\/sup><\/a> <\/sup>10<\/sup><\/a><\/sup><\/p>\n\n\n\n EMBO J.<\/em> 2026 Mar;45(5):1426-1459.doi: 10.1038\/s44318-025-00603-0. Epub 2025 Nov 3.<\/p>\n\n\n\n 1<\/sup>Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.<\/p>\n\n\n\n 2<\/sup>Institute of Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria.<\/p>\n\n\n\n 3<\/sup>Central Science Laboratory, College of Science and Engineering, University of Tasmania, Sandy Bay, TAS, 7005, Australia.<\/p>\n\n\n\n 4<\/sup>CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria.<\/p>\n\n\n\n 5<\/sup>Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.<\/p>\n\n\n\n 6<\/sup>Department of Chemical & Physical Sciences, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.<\/p>\n\n\n\n 7<\/sup>Institute of Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria. andreas.bergthaler@meduniwien.ac.at.<\/p>\n\n\n\n