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

Mol Oncol. 2024 Apr;18(4):866-894. doi: 10.1002/1878-0261.13351. Epub 2022 Dec 19.


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 p16INK4A (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 tumours from short-survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

Keywords: CDK4 Thr172‐phosphorylation; biomarker; cell cycle; mesothelioma; palbociclib; senescence‐associated secretory phenotype.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 4 / genetics
  • Humans
  • Mesothelioma* / drug therapy
  • Mesothelioma* / genetics
  • Mesothelioma* / metabolism
  • Mesothelioma, Malignant*
  • Phosphorylation
  • Pleural Neoplasms* / drug therapy
  • Pleural Neoplasms* / genetics


  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4