Purpose:

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft-tissue sarcoma that develops sporadically or in patients with neurofibromatosis type 1 (NF1). Its development is marked by the inactivation of specific tumor suppressor genes (TSG): NF1, CDKN2A, and SUZ12/EED (polycomb repressor complex 2). Each TSG loss can be targeted by particular drug inhibitors, and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs.

Experimental Design:

We performed a high-throughput screening in 3 MPNST cell lines testing 14 MEK inhibitors (MEKi), 11 cyclin-dependent kinase 4/6 inhibitors (CDKi), and 3 bromodomain inhibitors (BETi) as single agents and 147 pairwise co-treatments. Best combinations were validated in nine MPNST cell lines, and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse model. A final combination of the three inhibitor classes was tested in the same PDOX models.

Results:

A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi–BETi (ARRY-162 + I-BET151) co-treatment triggered a reduction in half of the NF1-related MPNST PDOXs and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST.

Conclusions:

Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi–BETi CDKi triple treatment elicits a significant reduction of human MPNST PDOXs.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Data S1

Combination indexes and curves for selected combinations and for all 9 MPNST cell lines

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Supplementary Figure S1

Dose response curves for all 28 single inhibitors in three independent MPNST cell lines

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Supplementary Figure S2

Dosages and administration schedule tested in PDOX models in a Maximum Tolerated Dose (MTD) test.

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Supplementary Figure S3

Status of the recurrent MPNST altered genes in 9 MPNSTs cell lines

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Supplementary Figure S4

Heatmap of pair-wise combination matrices obtained by High Throughput Screening

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Supplementary Figure S5

Combination Index plots for the 3 selected combos in the nine MPNST cell lines

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Supplementary Figure S6

Photographs of each individual tumor after the different co-treatments in vivo

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Supplementary Figure S7

Evaluation of three down or up regulated genes after BETi treatment in MPNST cell lines

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Supplementary Figure S8

Analysis of macrophage infiltration in MEKi-BETi co-treated MPNST PDOX tumors

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Supplementary Figure S9

Photographs of each individual tumor after the triple treatment in vivo

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Supplementary Figure S10

Analyses of the molecular targets of the triple treatment in vivo in NF1-18B MPNST PDOX

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Supplementary Figure S11

Analyses of the molecular targets of the triple treatment in vivo in SP-10 MPNST PDOX

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Supplementary Table S1

Table representing DBSumNeg and Excess HSA values from viability after 48h in the three MPNST cell lines tested

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Supplementary Table S2

Table summarizing the IC50 values of the nine drugs for each of the 9 MPNST cell lines

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Supplementary Table S3

List of the antibodies and primers used for Western Blot/Immunohistochemistry and RT-qPCR, respectively

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Supplementary Table S4

Synergy analysis of the 26 combinations validated in vitro in three MPNST cell lines

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