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

Wang, Jiawan ; Calizo, Ana ; Zhang, Lindy ; Pino, James C ; Lyu, Yang ; Pollard, Kai ; Zhang, Xiaochun ; Larsson, Alex T ; Conniff, Eric ; Llosa, Nicolas J ; Wood, David K ; Largaespada, David A ; Moody, Susan E ; Gosline, Sara J ; Hirbe, Angela C ; Pratilas, Christine A

Science advances, 2023-11, Vol.9 (47), p.eadg8876-eadg8876 [Periódico revisado por pares]

United States: AAAS

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  • Título:
    CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors
  • Autor: Wang, Jiawan ; Calizo, Ana ; Zhang, Lindy ; Pino, James C ; Lyu, Yang ; Pollard, Kai ; Zhang, Xiaochun ; Larsson, Alex T ; Conniff, Eric ; Llosa, Nicolas J ; Wood, David K ; Largaespada, David A ; Moody, Susan E ; Gosline, Sara J ; Hirbe, Angela C ; Pratilas, Christine A
  • Assuntos: 60 APPLIED LIFE SCIENCES ; cancer ; Cell Cycle ; Cell Line, Tumor ; Cyclin-Dependent Kinase 4 - genetics ; Humans ; MPNST ; Neurofibrosarcoma ; NF1 ; Signal Transduction
  • É parte de: Science advances, 2023-11, Vol.9 (47), p.eadg8876-eadg8876
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    SKCCC Cancer Center Core National Institutes of Health
    PNNL-SA-181806
    Children’s Cancer Foundation
    Hyundai Hope on Wheels
    NF Research Initiative
    USDOE
    Neurofibromatosis Therapeutic Acceleration Program
    Novartis Institute for Biomedical Research
    AC05-76RL01830
  • Descrição: 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 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.
  • Editor: United States: AAAS
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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