PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery, specifically targeting PTEN. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight elevated level of PTEN neddylation is markedly associated with resistance against Palbociclib, a CDK4/6 inhibitor used in HR+/HER2-breast cancer patients. Strikingly, we identified a potent inhibitor of PTEN neddylation which could obviously re-sensitized Palbociclib-therapy-resistant breast cancer. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more importantly, it stabilizes JUND by disrupting the interplay with its E3 ubiquitin ligase, ITCH. Therefore, the enhanced stability of JUND activates the AP-1/MAPK signaling pathway, resulting in the release of cytokines and chemokines, in turn, reprograming the tumor microenvironment, contributing to drug resistance, tumor recurrence and metastasis. This novel insight underscores the potential of targeting PTEN neddylation as a promising strategy for restoring the activity of key tumor suppressor and overcoming resistance in breast cancer therapy.