Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma
Abstract
Background: CIC -rearranged sarcoma is a rare and highly aggressive cancer that primarily affects children and young adults and has few effective treatment options. Previous studies have identified molecular dependence on cyclin-dependent kinase 2 (CDK2), but additional therapeutic vulnerabilities remain poorly defined. Here, we investigate the activity of CDK2-targeted therapies and evaluate combination strategies using new patient-derived models of CIC -rearranged sarcoma.
Methods: We established patient-derived cell lines and matching xenograft models from tumors harboring CIC::DUX4 and CIC::NUTM1 fusions, with xenograft studies performed in 7-week-old female NSG mice. We assessed the effects of CDK2 inhibition alone and in combination with cyclin-dependent kinase 9 (CDK9) inhibition using molecular, functional, and transcriptomic analyses in vitro and in vivo.
Results: Here we show that CIC -rearranged sarcoma depends on the MYC oncogene and is vulnerable to CDK2 inhibition. The CDK2 inhibitor tagtociclib suppresses MYC-regulated gene expression, inhibits tumor cell proliferation, and reduces tumor growth in patient-derived models. Combined inhibition of CDK2 and CDK9 produces synergistic anti-tumor activity by further suppressing MYC-driven transcription, enhancing apoptotic cell death, and improving tumor control in vitro and in vivo.
Conclusions: These findings identify MYC-driven transcription as a therapeutic vulnerability in CIC -rearranged sarcoma and support combined CDK2 and CDK9 inhibition as a promising treatment strategy. The patient-derived models established in this study also provide valuable resources for future preclinical and translational research.
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BibTeX
@article{odomlewis2026cotargeting,
title = {{Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma}},
author = {Quentin Odom-Lewis and Samantha L. Davis and Stephan Pieper and Shannon M. R. Legge and Emilia F. A. Regenfuss and Nicolas Fernandez and Phillip D. Michaels and João A. Paulo and Steven P. Gygi and Chen Chu and Shanshan Zheng and Paola Dal Cin and Jason L. Hornick and Nicole L. Solimini and Timothy B. Branigan and Mohamed Alyousef and Emanuele Mazzola and Ewa T. Sicinska and Karen Bui and Prafulla C. Gokhale and Christopher A. French and George D. Demetri and Geoffrey I. Shapiro and Inga-Marie Schaefer},
journal = {Communications Medicine},
year = {2026},
month = oct,
doi = {10.1038/s43856-026-01956-1},
url = {https://www.nature.com/articles/s43856-026-01956-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma
AU - Quentin Odom-Lewis
AU - Samantha L. Davis
AU - Stephan Pieper
AU - Shannon M. R. Legge
AU - Emilia F. A. Regenfuss
AU - Nicolas Fernandez
AU - Phillip D. Michaels
AU - João A. Paulo
AU - Steven P. Gygi
AU - Chen Chu
AU - Shanshan Zheng
AU - Paola Dal Cin
AU - Jason L. Hornick
AU - Nicole L. Solimini
AU - Timothy B. Branigan
AU - Mohamed Alyousef
AU - Emanuele Mazzola
AU - Ewa T. Sicinska
AU - Karen Bui
AU - Prafulla C. Gokhale
AU - Christopher A. French
AU - George D. Demetri
AU - Geoffrey I. Shapiro
AU - Inga-Marie Schaefer
PY - 2026
DA - 2026/10/07
JO - Communications Medicine
DO - 10.1038/s43856-026-01956-1
UR - https://www.nature.com/articles/s43856-026-01956-1
AB - Background: CIC -rearranged sarcoma is a rare and highly aggressive cancer that primarily affects children and young adults and has few effective treatment options. Previous studies have identified molecular dependence on cyclin-dependent kinase 2 (CDK2), but additional therapeutic vulnerabilities remain poorly defined. Here, we investigate the activity of CDK2-targeted therapies and evaluate combination strategies using new patient-derived models of CIC -rearranged sarcoma. Methods: We established patient-derived cell lines and matching xenograft models from tumors harboring CIC::DUX4 and CIC::NUTM1 fusions, with xenograft studies performed in 7-week-old female NSG mice. We assessed the effects of CDK2 inhibition alone and in combination with cyclin-dependent kinase 9 (CDK9) inhibition using molecular, functional, and transcriptomic analyses in vitro and in vivo. Results: Here we show that CIC -rearranged sarcoma depends on the MYC oncogene and is vulnerable to CDK2 inhibition. The CDK2 inhibitor tagtociclib suppresses MYC-regulated gene expression, inhibits tumor cell proliferation, and reduces tumor growth in patient-derived models. Combined inhibition of CDK2 and CDK9 produces synergistic anti-tumor activity by further suppressing MYC-driven transcription, enhancing apoptotic cell death, and improving tumor control in vitro and in vivo. Conclusions: These findings identify MYC-driven transcription as a therapeutic vulnerability in CIC -rearranged sarcoma and support combined CDK2 and CDK9 inhibition as a promising treatment strategy. The patient-derived models established in this study also provide valuable resources for future preclinical and translational research.
SN - 2730-664X
ER -