Perk mediates tumor cell fate and therapeutic outcome in response to CDK4/6 inhibition

Dysregulation of cyclin-dependent kinase 4/6 (CDK4/6) occurs in cancer and is targeted by CDK4/6 inhibitors (CDK4/6i) including palbociclib (PD). CDK4/6i triggers quiescence (reversible) which transitions to senescence (irreversible) following prolonged exposure. Resolving the program that directs this transition is critical to overcoming CDK4/6i resistance and improving the efficacy of CDK4/6 inhibitors. We demonstrate that CDK4/6i predominantly triggers PERK, a shared kinase between the unfolded protein response (UPR) and integrated stress response (ISR). Inhibition of PERK combined with CDK4/6i impairs UPR/ISR adaptive signaling instructing early commitment to senescence. Early senescence commitment reflects accelerated senescence markers, dephosphorylation of the Retinoblastoma (RB), and engagement of a senescence specific gene signature. Combined treatment with CDK4/6i and ISRIB (ISR inhibitor) reduces tumor growth more effectively than single agents through increased senescence and immune cell surveillance. This work highlights CDK4/6i+ISRIB as a potential therapy for a range of cancers with an intact CDK4/6-RB1 axis. CDK4/6 inhibitors can trigger stress responses that alter tumor outcomes. Here, the authors show that PERK signaling shapes cell fate after CDK4/6 inhibition and influences response to therapy.

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Publication Details

Journal
Nature Communications
Published
2026-10-17
DOI
https://doi.org/10.1038/s41467-026-78698-0
Primary Topic
Advanced Breast Cancer Therapies
Type
article
Field-Weighted Citation Impact
0.00

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article

Perk mediates tumor cell fate and therapeutic outcome in response to CDK4/6 inhibition

Serge Yu. Fuchs, Kwok‐Kin Wong, Shuyuan Zhang, Anil K. Rustgi et al.
Nature Communications
Advanced Breast Cancer Therapies
article

Perk mediates tumor cell fate and therapeutic outcome in response to CDK4/6 inhibition

Serge Yu. Fuchs, Kwok‐Kin Wong, Shuyuan Zhang, Anil K. Rustgi, Davide Ruggero, Masataka Shimonosono, John Alan Diehl, Bartosz Mucha, Ata Abbas, Hiroshi Nakagawa, Marganit Farago, Dariusz Pytel, Brian S. Henick, Constantinos Koumenis, Polly J. Phillips‐Mason, Debora Cavero, Yi Fan, Varun Samudra
article en

Abstract

Dysregulation of cyclin-dependent kinase 4/6 (CDK4/6) occurs in cancer and is targeted by CDK4/6 inhibitors (CDK4/6i) including palbociclib (PD). CDK4/6i triggers quiescence (reversible) which transitions to senescence (irreversible) following prolonged exposure. Resolving the program that directs this transition is critical to overcoming CDK4/6i resistance and improving the efficacy of CDK4/6 inhibitors. We demonstrate that CDK4/6i predominantly triggers PERK, a shared kinase between the unfolded protein response (UPR) and integrated stress response (ISR). Inhibition of PERK combined with CDK4/6i impairs UPR/ISR adaptive signaling instructing early commitment to senescence. Early senescence commitment reflects accelerated senescence markers, dephosphorylation of the Retinoblastoma (RB), and engagement of a senescence specific gene signature. Combined treatment with CDK4/6i and ISRIB (ISR inhibitor) reduces tumor growth more effectively than single agents through increased senescence and immune cell surveillance. This work highlights CDK4/6i+ISRIB as a potential therapy for a range of cancers with an intact CDK4/6-RB1 axis. CDK4/6 inhibitors can trigger stress responses that alter tumor outcomes. Here, the authors show that PERK signaling shapes cell fate after CDK4/6 inhibition and influences response to therapy.

Nature Communications
Kagoshima University (JP), Medical University of South Carolina (US), University of California, San Francisco (US), Columbia University Irving Medical Center (US), NYU Langone Health (US), Medical University of Lodz (PL), Case Western Reserve University (US), University of Pennsylvania (US)
Narodowe Centrum Nauki, Stand Up To Cancer, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 12%
Advanced Breast Cancer Therapies
DOIOpen Access PDFOpenAlex
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