CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer

Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during ra...

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Main Authors: Carlos M Roggero, Anwesha B Ghosh, Anvita Devineni, Shihong Ma, Eliot Blatt, Ganesh V. Raj, Yi Yin
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:Translational Oncology
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Online Access:http://www.sciencedirect.com/science/article/pii/S1936523324003577
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author Carlos M Roggero
Anwesha B Ghosh
Anvita Devineni
Shihong Ma
Eliot Blatt
Ganesh V. Raj
Yi Yin
author_facet Carlos M Roggero
Anwesha B Ghosh
Anvita Devineni
Shihong Ma
Eliot Blatt
Ganesh V. Raj
Yi Yin
author_sort Carlos M Roggero
collection DOAJ
description Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.
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spelling doaj-art-df6a0cd7738e44f882139384f25dd5ff2025-01-22T05:41:24ZengElsevierTranslational Oncology1936-52332025-02-0152102231CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancerCarlos M Roggero0Anwesha B Ghosh1Anvita Devineni2Shihong Ma3Eliot Blatt4Ganesh V. Raj5Yi Yin6Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Instituto de Histología y Embriología de Mendoza (IHEM)-CONICET-Universidad Nacional de Cuyo, ArgentinaDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Corresponding author at: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.http://www.sciencedirect.com/science/article/pii/S1936523324003577DNA damage repairCDK4/6 inhibitionPARP inhibitionPatient-derived explantNon-small cell lung cancer
spellingShingle Carlos M Roggero
Anwesha B Ghosh
Anvita Devineni
Shihong Ma
Eliot Blatt
Ganesh V. Raj
Yi Yin
CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
Translational Oncology
DNA damage repair
CDK4/6 inhibition
PARP inhibition
Patient-derived explant
Non-small cell lung cancer
title CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
title_full CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
title_fullStr CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
title_full_unstemmed CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
title_short CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer
title_sort cdk4 6 inhibitors promote parp1 degradation and synergize with parp inhibitors in non small cell lung cancer
topic DNA damage repair
CDK4/6 inhibition
PARP inhibition
Patient-derived explant
Non-small cell lung cancer
url http://www.sciencedirect.com/science/article/pii/S1936523324003577
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