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Updated: Jul 10, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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

Jiawan Wang1, Ana Calizo1, Lindy Zhang1

  • 1Division 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.

Science Advances
|November 24, 2023
PubMed

Insights

Combining SHP2 inhibitors with CDK4/6 inhibitors shows promise for treating malignant peripheral nerve sheath tumors (MPNSTs). This dual-drug approach enhances anti-tumor activity and supports clinical advancement for MPNST and NF1-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor prognoses.
  • Limited effective therapeutic options necessitate novel treatment strategies for MPNSTs.

Purpose of the Study:

  • To investigate the antiproliferative effects of SHP2 inhibition in MPNSTs.
  • To evaluate the efficacy of combining a SHP2 inhibitor (TNO155) with a CDK4/6 inhibitor (CDK4/6i) to overcome resistance and enhance anti-tumor activity.

Main Methods:

  • Genetic depletion of PTPN11 and pharmacological inhibition using SHP2 inhibitor TNO155.
  • Assessment of signaling pathways, including RB function, in response to SHP2 inhibition.
  • Combination therapy studies with TNO155 and a CDK4/6 inhibitor in in vitro and in vivo MPNST models.

Main Results:

  • SHP2 inhibition (TNO155) demonstrated antiproliferative effects in MPNST models.
  • Resistance to TNO155 was partially mediated by reduced RB function.
  • The combination of TNO155 and CDK4/6i synergistically enhanced anti-tumor activity, suppressed cell cycle progression, and reduced inhibitor-of-apoptosis proteins, leading to more durable responses.

Conclusions:

  • The combination of SHP2 and CDK4/6 inhibitors offers a potent therapeutic strategy for MPNSTs.
  • This combination strategy shows potential for clinical advancement in MPNST and other NF1-driven tumors.

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