CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors-Reference-Cited by-同舟云学术

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

Published:2023-11-24 Issue:47 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Wang Jiawan¹^ORCID,Calizo Ana¹^ORCID,Zhang Lindy¹^ORCID,Pino James C.²^ORCID,Lyu Yang³^ORCID,Pollard Kai¹,Zhang Xiaochun³,Larsson Alex T.⁴^ORCID,Conniff Eric⁵,Llosa Nicolas J.¹^ORCID,Wood David K.⁵^ORCID,Largaespada David A.⁴^ORCID,Moody Susan E.⁶^ORCID,Gosline Sara J.²^ORCID,Hirbe Angela C.³^ORCID,Pratilas Christine A.¹^ORCID

Affiliation:

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

2. Pacific Northwest National Laboratory (PNNL), Seattle, WA, USA.

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

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

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

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

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the 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 antiproliferative 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 antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adg8876

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