Investigation of signalling pathways and potential mechanisms of drug resistance associated with the two transmissible cancers in the Tasmanian devil using phosphoproteomics

Investigation of signalling pathways and potential mechanisms of drug resistance associated with the two transmissible cancers in the Tasmanian devil using phosphoproteomics Two transmissible cancers, Devil Facial Tumor 1 (DFT1) and Devil Facial Tumor 2 (DFT2), have caused significant declines in Tasmanian devil populations. DFT1 is driven by ERBB tyrosine kinases, immune evasion through MHCI downregulation and can be targeted by ERBB inhibition. In contrast, DFT2 is susceptible to PDGFR inhibition. We show that both tumors exhibit changes in upstream kinase phosphorylation but activate common downstream pathways, enabling rapid development of escape mechanisms. DFT1 shifts toward a more mesenchymal phenotype and PDGFR signaling when ERBB is inhibited, resembling DFT2, while DFT2 adapts to mimic ERBB/STAT3 signaling and MHCI-related immune evasion when PDGFR is inhibited, resembling DFT1. This tumor plasticity, particularly in DFT2, mirrors changes observed in the wild, offering insights into the future evolution of these cancers. Importantly, combination treatments targeting both pathways show synergistic effects, providing a potential strategy for conservation efforts for the endangered Tasmanian devil.