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

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

doi:10.1126/SCIADV.ADG8876

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

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

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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.

Original language	English (US)
Article number	adg8876
Journal	Science Advances
Volume	9
Issue number	47
DOIs	https://doi.org/10.1126/SCIADV.ADG8876
State	Published - Nov 2023

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Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wang, J., Calizo, A., Zhang, L., Pino, J. C., Lyu, Y., Pollard, K., Zhang, X., Larsson, A. T., Conniff, E., Llosa, N. J., Wood, D. K., Largaespada, D. A., Moody, S. E., Gosline, S. J., Hirbe, A. C., & Pratilas, C. A. (2023). CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors. Science Advances, 9(47), Article adg8876. https://doi.org/10.1126/SCIADV.ADG8876

Wang, J, Calizo, A, Zhang, L, Pino, JC, Lyu, Y, Pollard, K, Zhang, X, Larsson, AT, Conniff, E, Llosa, NJ, Wood, DK , Largaespada, DA, Moody, SE, Gosline, SJ, Hirbe, AC & Pratilas, CA 2023, 'CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors', Science Advances, vol. 9, no. 47, adg8876. https://doi.org/10.1126/SCIADV.ADG8876

@article{01b7890008e74425a95283977667233c,

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

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

year = "2023",

month = nov,

doi = "10.1126/SCIADV.ADG8876",

language = "English (US)",

volume = "9",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "47",

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TY - JOUR

T1 - CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors

AU - Wang, Jiawan

AU - Calizo, Ana

AU - Zhang, Lindy

AU - Pino, James C.

AU - Lyu, Yang

AU - Pollard, Kai

AU - Zhang, Xiaochun

AU - Larsson, Alex T

AU - Conniff, Eric

AU - Llosa, Nicolas J.

AU - Wood, David K.

AU - Largaespada, David A.

AU - Moody, Susan E.

AU - Gosline, Sara J.

AU - Hirbe, Angela C.

AU - Pratilas, Christine A.

N1 - Publisher Copyright: Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

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VL - 9

JO - Science Advances

JF - Science Advances

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

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

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