Computational drug repositioning of bortezomib to reverse metastatic effect ofGALNT14in lung cancer
AbstractAlthough many molecular targets for cancer therapy have been discovered, they often show poor druggability, which is a major obstacle to develop targeted drugs. As an alternative route to drug discovery, we adopted anin silicodrug repositioning (in silicoDR) approach based on large-scale gene expression signatures, with the goal of identifying inhibitors of lung cancer metastasis. Our analysis of clinicogenomic data identified GALNT14, an enzyme involved in O-linked N-acetyl galactosamine glycosylation, as a putative driver of lung cancer metastasis leading to poor survival. To overcome the poor druggability of GALNT14, we leveraged Connectivity Map approach, anin silicoscreening for drugs that are likely to revert the metastatic expression patterns. It leads to identification of bortezomib (BTZ) as a potent metastatic inhibitor, bypassing direct inhibition of poorly druggable target, GALNT14. The anti-metastatic effect of BTZ was verifiedin vitroandin vivo. Notably, both BTZ treatment andGALNT14knockdown attenuated TGFβ-mediated gene expression and suppressed TGFβ-dependent metastatic genes, suggesting that BTZ acts by modulating TGFβ signalingTaken together, these results demonstrate that ourin silicoDR approach is a viable strategy to identify a candidate drug for undruggable targets, and to uncover its underlying mechanisms.