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

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 inhi...

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Published in:Science advances 2023-11, Vol.9 (47), p.eadg8876-eadg8876
Main Authors: 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
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
cancer
Cell Cycle
Cell Line, Tumor
Cyclin-Dependent Kinase 4 - genetics
Humans
MPNST
Neurofibrosarcoma
NF1
Signal Transduction
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/SCIADV.ADG8876