Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation
Aldonza, M. B. D.; Cha, J.; Yong, I.; Ku, J.; Lee, D.; Sinitcyn, P.; Cho, R.-E.; Delos Reyes, R. D.; Kim, D.; Sung, H.-J.; Kim, S.; Kang, M.; Ku, Y.; Park, G.; Ryu, H. S.; Cho, S.; Kim, T. M.; Kim, P.; Cho, J.-Y.; Kim, Y.
Show abstract
Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post-translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy-induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- CDK4 inactivation balances resistance to apoptosis with heightened metabolic sensitivity in triple negative breast cancer cells 95%
- FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell 95%
- A novel non-catalytic scaffolding activity of Hexokinase 2 contributes to EMT and metastasis 95%
Similar papers in this journal
- Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma 97%
- A new universal chimeric-antigen receptor (CAR)- fragment antibody binder (FAB) split system for cancer immunotherapy 96%
- MLL1 regulates cytokine-driven cell migration and metastasis 95%
Similar papers in this journal
- GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis 95%
- UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFRsignaling 95%
- Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer 95%
Similar papers in this journal
- A Cancer-Specific Antigen Drives Histone Acetylation by Stabilizing the Acetyltransferases 95%
- P-cadherin mechanoactivates tumor- mesothelium metabolic coupling to promote ovarian cancer metastasis 95%
- An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade 95%
Similar papers in this journal
- Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation 95%
- NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy 95%
- Neoplastic immune mimicry potentiates breast tumor progression 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.