Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition - Centre de recherche des Cordeliers Access content directly
Journal Articles Molecular Oncology Year : 2023

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition

Myriam Remmelink
  • Function : Author
  • PersonId : 910390
Nolwenn Le-Stang
Thierry Berghmans
  • Function : Author
  • PersonId : 1080655
Didier Jean

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16(INK4A) (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumors from short survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.
Fichier principal
Vignette du fichier
2022 Paternot et al, Molecular Oncology.pdf (3.76 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-03898858 , version 1 (02-11-2023)

Identifiers

Cite

Sabine Paternot, Eric Raspé, C Meiller, Maxime Tarabichi, Jean-Baptiste Assié, et al.. Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition. Molecular Oncology, In press, ⟨10.1002/1878-0261.13351⟩. ⟨hal-03898858⟩
42 View
28 Download

Altmetric

Share

Gmail Facebook X LinkedIn More