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Characterization by RNAseq of malignant pleural mesothelioma cell lines and their response to palbociclib

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in established MPM cell lines using a variety of approaches including RNA sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 4 of 6 cell lines. In a parallel study, the efficacy of palbociclib was confirmed in a large panel of patient-derived cell lines indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4, which was associated with the high p16 levels that accompany RB1 defects or inactivation, and also (unexpectely) CCNE1 overexpression in the presence of WT RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype (SASP) including various potentially immunogenic components was also irreversibly induced. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment including in several combinatorial therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195568 | GEO | 2022/12/20

REPOSITORIES: GEO

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

Project description:Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a large panel of MPM cell lines, including 19 patient-derived primary cell lines, using a variety of approaches including RNA sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 out of 28 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 overexpression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype (SASP) including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.

| EGAS00001006117 | EGA

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Project description:Despite overall good prognosis associated to thyroid cancer, poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated thyoid carcinomas (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 thyroid cancer cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels that were associated with proliferative activity. One of the main mechanisms of resistance to CDK4/6i is RB1 defects or inactivation. RB1 mutations were present in the 3 insensitive cell lines but were not found in 5 of the 7 tumors without phosphorylated CDK4. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors and cell lines lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.

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2019-08-23 | GSE133567 | GEO

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2020-03-25 | PXD005611 | Pride

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