Revisiting AXL as a therapeutic target in soft tissue sarcoma: transcriptomic profiling reveals largely AXL-independent activity of dubermatinib and bemcentinib

Abstract

Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal malignancies with generally poor prognosis, raising a continued interest in novel therapeutic targets. The TAM-family receptor tyrosine kinase AXL has been proposed as a therapeutic target across several cancer types, including STS. Here we revisit the clinical relevance of AXL in STS by combining in silico analyses with functional and transcriptomic characterisation of two AXL inhibitors, dubermatinib and bemcentinib, in HT-1080 and SK-LMS-1 cells. STS ranked among the tumour types with the highest median AXL mRNA expression across The Cancer Genome Atlas, yet AXL expression was not associated with patient survival. Both inhibitors reduced cell viability and induced apoptosis but, unexpectedly, shRNA-mediated AXL knockdown didn't reproduce their antiproliferative effect nor modified sensitivity to either drug. Transcriptomic profiling showed weak correlation between knockdown- and drug-induced changes, with most drug-regulated genes being AXL-independent and largely cell line-specific. Connectivity analysis against LINCS, regulatory-network inference and CRISPR dependency data instead point to mitotic and PI3K-mTOR pathways as candidate mediators of the therapeutic activity. Thus, dubermatinib and bemcentinib show antitumour activity in STS models that is largely independent of AXL inhibition, suggesting that the rationale for AXL-directed therapy may be reconsidered.