Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion.

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ICR Authors

Roulstone, Victoria
 Wright, James
 Melake, Johanna Miriam
 Choudhary, Jyoti
 Lord, Christopher
 Chauhan, Ritika
 Chan Wah Hak, Charleen Min Li
 Nenclares, Pablo
 Rullan, Antonio
 Meier, Pascal
 Melcher, Alan
 Harrington, Kevin

Authors

Roulstone, V
Kyula-Currie, J
Wright, J
Patin, EC
Dean, I
Yu, L
Barreiro-Alonso, A
Melake, M
Choudhary, J
Elliott, R
Lord, CJ
Mansfield, D
Matthews, N
Chauhan, R
Jennings, V
Chan Wah Hak, C
Baldock, H
Butera, F
Appleton, E
Nenclares, P
Pedersen, M
Foo, S
Wongariyapak, A
Rullan, A
Tenev, T
Meier, P
Vile, R
Pandha, H
Melcher, A
McLaughlin, M
Harrington, KJ

Document Type

Journal Article

Date

2025-05-25

Date Accepted

2025-05-15

Abstract

Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.

Citation

Nature Communications, 2025, 16 (1), pp. 4855 -

DOI

10.1038/s41467-025-60133-5

URI

https://repository.icr.ac.uk/handle/internal/6641

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Communications

Publisher

NATURE PORTFOLIO

ISSN

2041-1723

eISSN

2041-1723

Collections

Breast Cancer Research

Research Team

Targeted Therapy
Functional Proteomics
Prote & Metabolomics Fac
Precision Oncology Lord
Trans Immunotherapy

Cell Death and Immunity

Notes