phaidra.vetmeduni.ac.at o:5393 DOI 10.1038/s44318-025-00603-0 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 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. eng Devil Facial Tumour Disease Phosphoproteomics Transmissible Cancer Tyrosine Kinase Inhibitor Resistance Combination Therapy 2026-08-05T08:32:21.737Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Schönbichler;Anna; FN:Anna Schönbichler X-ORCID:https://orcid.org/0009-0001-5914-7782 END:VCARD BEGIN:VCARD VERSION:3.0 N:Orlova;Anna; FN:Anna Orlova X-ORCID:https://orcid.org/0000-0001-9262-7529 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kreindl;Carmen; FN:Carmen Kreindl END:VCARD BEGIN:VCARD VERSION:3.0 N:Endler;Lukas; FN:Lukas Endler X-ORCID:https://orcid.org/0000-0002-9115-8756 END:VCARD BEGIN:VCARD VERSION:3.0 N:Wilson;Richard; FN:Richard Wilson X-ORCID:https://orcid.org/0000-0003-0152-4394 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kosack;Lindsay; FN:Lindsay Kosack END:VCARD BEGIN:VCARD VERSION:3.0 N:Hofmann;Anna; FN:Anna Hofmann END:VCARD BEGIN:VCARD VERSION:3.0 N:Viczenczova;Csilla; FN:Csilla Viczenczova END:VCARD BEGIN:VCARD VERSION:3.0 N:Darby;Jocelyn; FN:Jocelyn Darby END:VCARD BEGIN:VCARD VERSION:3.0 N:Erdogan;Fettah; FN:Fettah Erdogan X-ORCID:https://orcid.org/0000-0002-6968-4821 END:VCARD BEGIN:VCARD VERSION:3.0 N:Patchett;Amanda L; FN:Amanda L Patchett END:VCARD BEGIN:VCARD VERSION:3.0 N:Koren;Anna; FN:Anna Koren END:VCARD BEGIN:VCARD VERSION:3.0 N:Kubicek;Stefan; FN:Stefan Kubicek X-ORCID:https://orcid.org/0000-0003-0855-8343 END:VCARD BEGIN:VCARD VERSION:3.0 N:Müller;Mathias; FN:Mathias Müller X-ORCID:https://orcid.org/0000-0002-7879-3552 END:VCARD BEGIN:VCARD VERSION:3.0 N:Flies;Andrew S; FN:Andrew S Flies X-ORCID:https://orcid.org/0000-0002-4550-1859 END:VCARD BEGIN:VCARD VERSION:3.0 N:Bergthaler;Andreas; FN:Andreas Bergthaler X-ORCID:https://orcid.org/0000-0003-0597-1976 END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl X-ORCID:https://orcid.org/0000-0003-0918-9463 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 8426232 https://phaidra.vetmeduni.ac.at/o:5393 https://phaidra.vetmeduni.ac.at/api/object/o:5393/thumbnail LOMv1.0 discipline