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.
Authors
- Amanda L. Patchett (ORCID: https://orcid.org/0000-0002-8424-4680)
- Lukas Endler (ORCID: https://orcid.org/0000-0002-9115-8756)
- Mathias Müller (ORCID: https://orcid.org/0000-0002-7879-3552)
- Richard Moriggl (ORCID: https://orcid.org/0000-0003-0918-9463)
- Csilla Viczenczová
- Jocelyn M. Darby (ORCID: https://orcid.org/0000-0002-1819-6000)
- Anna Koren (ORCID: https://orcid.org/0000-0003-2528-4970)
- Lindsay Kosack (ORCID: https://orcid.org/0000-0001-7266-0006)
- Richard Wilson (ORCID: https://orcid.org/0000-0003-0152-4394)
- Andreas Bergthaler (ORCID: https://orcid.org/0000-0003-0597-1976)
- Fettah Erdogan (ORCID: https://orcid.org/0000-0002-6968-4821)
- Anna Schönbichler (ORCID: https://orcid.org/0009-0001-5914-7782)
- Anna Orlova (ORCID: https://orcid.org/0000-0001-9262-7529)
- Andrew S. Flies (ORCID: https://orcid.org/0000-0002-4550-1859)
- Stefan Kubicek (ORCID: https://orcid.org/0000-0003-0855-8343)
- Anna Hofmann (ORCID: https://orcid.org/0000-0002-4480-6028)
- Carmen Kreindl
Institutions
- University of Tasmania (AU)
- Austrian Academy of Sciences (AT)
- University of Veterinary Medicine Vienna (AT)
- University of Salzburg (AT)
- University of Toronto (CA)
- Amgen (Canada) (CA)
- CeMM Research Center for Molecular Medicine (AT)
- Tasmanian Land Conservancy (AU)
- Medical University of Vienna (AT)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s44318-025-00603-0
- Citations
- 2
- Primary Topic
- Veterinary Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Veterinärmedizinische Universität Wien