New biomarker identified for therapeutic intervention for reducing tumor progression
The result of years of collaboration between CCBIO PI Jim Lorens and Rolf Brekken and other colleagues in the USA, Finland, Romania and Norway, is now published in Science Signaling, with research identifying nuclear AKT3 as a new biomarker of advanced malignancy and revealing the pathway that activates AKT3 to drive epithelial-to-mesenchymal transition in pancreatic cancer.
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The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). In this work, Arner et al. showed that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, this showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon activation, AKT3 interacted with and promoted the nuclear accumulation of Snail, which led to increased EMT as assessed by marker abundance. In human pancreatic ductal adenocarcinoma tissue, nuclear AKT3 co-localized with Snail and correlated with worse clinical outcomes. Primary mouse pancreatic cancer cells deficient in AKT3 showed reduced metastatic spread in vivo, suggesting selective AKT3 inhibition as a potential therapeutic avenue for targeting EMT in aggressive cancers.
Possible target for many cancers
Tumor cell expression of AXL is prevalent in many tumor types including pancreatic, breast and lung cancer where it is appreciated that AXL drives tumor progression. AXL is widely expressed in malignancy and the AXL-TBK1-AKT3 is likely an important driver of metastasis and drug resistance in several cancers. Using comprehensive analyses of pancreatic and breast cancer cell lines alongside patient tumor samples, nuclear AKT3 was identified as a pivotal regulator of EMT in these malignancies. Importantly, the findings suggest that selectively targeting AKT3 could represent a promising therapeutic strategy to combat these highly invasive cancers, offering new avenues for clinical intervention.
A result of a longstanding collaboration
This builds on previous work in the Brekken and Lorens labs on identifying how AXL promotes tumor progression. The Brekken lab identified that TBK1 is downstream of AXL in a prior publication (PMID: 30938713). The Lorens lab at CCBIO along with BerGenBio ASA developed a novel AKT3 inhibitor, which was exploited in the current study. Brekken has been affiliated with CCBIO through its international faculty since 2016, facilitating international collaboration with CCBIO’s groups.
See link to the publication “AXL-TBK1 driven AKT3 activation promotes metastasis” here.