Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Kudo, Rei; Safonov, Anton; Jones, Catherine; Moiso, Enrico; Dry, Jonathan R.; Shao, Hong; Nag, Sharanya; da Silva, Edaise M.; Yildirim, Selma Yeni; Li, Qing; O'Connell, Elizabeth; Patel, Payal; Will, Marie; Fushimi, Atsushi; Benitez, Marimar; Bradic, Martina; Fan, Li; Nakshatri, Harikrishna; Sudhan, Dhivya R.; Denz, Christopher R.; Huerga Sanchez, Iker; Reis-Filho, Jorge S.; Goel, Shom; Koff, Andrew; Weigelt, Britta; Khan, Qamar J.; Razavi, Pedram; Chandarlapaty, Sarat

doi:10.1016/j.ccell.2024.09.009

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Cited by 3 publications

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CDK4/6 inhibitors in HR-positive breast cancer immunotherapy

Shen,

Ma,

Zhu

et al. 2025

Bioorganic Chemistry

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CDK4/6 inhibitors in HR-positive breast cancer immunotherapy

Shen,

Ma,

Zhu

et al. 2025

Bioorganic Chemistry

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Targeting CDK2 to circumvent treatment resistance in HR+ breast cancer

Arrizabalaga,

García-Torralba,

Galluzzi

et al. 2024

Trends in Molecular Medicine

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PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

Liu,

Tan

et al. 2024

Preprint

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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.

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Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Cited by 3 publications

References 85 publications

CDK4/6 inhibitors in HR-positive breast cancer immunotherapy

CDK4/6 inhibitors in HR-positive breast cancer immunotherapy

Targeting CDK2 to circumvent treatment resistance in HR+ breast cancer

PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

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