Enhanced radiotherapy susceptibility in NSCLC through palbociclib-mediated PP5 inhibition

Chao-Yuan Huang; Li-Ju Chen; Grace Chen; Cheng-Yi Wang; Shiao-Ya Hong

doi:10.1016/j.bbamcr.2024.119884

Enhanced radiotherapy susceptibility in NSCLC through palbociclib-mediated PP5 inhibition

Biochim Biophys Acta Mol Cell Res. 2024 Nov 30;1872(2):119884. doi: 10.1016/j.bbamcr.2024.119884. Online ahead of print.

Authors

Chao-Yuan Huang¹, Li-Ju Chen¹, Grace Chen², Cheng-Yi Wang³, Shiao-Ya Hong⁴

Affiliations

¹ Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100229, Taiwan.
² School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
³ Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 231009, Taiwan. Electronic address: cywang@mospital.com.
⁴ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan. Electronic address: shaline@nycu.edu.tw.

PMID: 39617046
DOI: 10.1016/j.bbamcr.2024.119884

Abstract

Radiotherapy remains a cornerstone in the treatment of non-small cell lung cancer (NSCLC), yet radioresistance often limits its efficacy. Identifying molecular targets that enhance radiosensitivity is crucial to offering both curative and palliative benefits for patients with NSCLC. Utilizing bioinformatics analysis, our study revealed significantly higher expression of PP5 in NSCLC tissues compared to normal tissues. Kaplan-Meier survival analysis also showed that high PP5 expression correlates with poorer overall survival, particularly in patients undergoing radiotherapy, suggesting a role for PP5 in radioresistance. We further demonstrated that PP5 is a critical target of palbociclib, distinct from CDK4/6, influencing radiosensitivity in NSCLC. Palbociclib enhanced radiotherapy susceptibility by inducing sustained DNA damage and AMPK activation. The subsequent cellular event is apoptosis rather than autophagy. Furthermore, the enhanced efficacy of combination therapy was counteracted by an AMPK inhibitor and PP5 activator, underscoring the importance of these pathways in mediating the response. Our findings provide compelling evidence that targeting PP5 can significantly enhance the therapeutic outcomes of radiotherapy in NSCLC. This research offers valuable insights into new combination therapy strategies, highlighting the potential of PP5 as a novel therapeutic target to overcome radioresistance.

Keywords: AMPK; NSCLC; PP5; Palbociclib; Radiotherapy.