CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors.

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
03 Feb 2023
Historique:
pubmed: 14 2 2023
medline: 14 2 2023
entrez: 13 2 2023
Statut: epublish

Résumé

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its anti-proliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable anti-tumor activity in

Identifiants

DOI: 10.1101/2023.02.02.526674 PMID: 36778419 PMC: PMC9915673
pubmed: 36778419
doi: 10.1101/2023.02.02.526674
pmc: PMC9915673
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States

Commentaires et corrections

Type : UpdateIn

Déclaration de conflit d'intérêts

Competing interests: JW, SEM and CAP have a pending patent related to this study. The authors have no additional financial interests.

Auteurs

Jiawan Wang (J)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

Ana Calizo (A)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

Lindy Zhang (L)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

James C Pino (JC)

Pacific Northwest National Laboratory; Seattle, WA, USA.

Yang Lyu (Y)

Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis; St. Louis, MO, USA.

Kai Pollard (K)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

Xiaochun Zhang (X)

Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis; St. Louis, MO, USA.

Alex T Larsson (AT)

Department of Pediatrics, Masonic Cancer Center, University of Minnesota; Minneapolis, MN, USA.

Eric Conniff (E)

Department of Biomedical Engineering, University of Minnesota; Minneapolis, MN, USA.

Nicolas Llosa (N)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

David K Wood (DK)

Department of Biomedical Engineering, University of Minnesota; Minneapolis, MN, USA.

David A Largaespada (DA)

Department of Pediatrics, Masonic Cancer Center, University of Minnesota; Minneapolis, MN, USA.

Susan E Moody (SE)

Novartis Institutes for Biomedical Research; Cambridge, MA, USA.

Sara J Gosline (SJ)

Pacific Northwest National Laboratory; Seattle, WA, USA.

Angela C Hirbe (AC)

Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. Louis; St. Louis, MO, USA.

Christine A Pratilas (CA)

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Baltimore, MD, USA.

Classifications MeSH