Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer.

Autor: Powell RT; Center for Translational Cancer Research, Institute of Bioscience and Technology Texas A&M Health Science Center, Houston, TX, USA., Rinkenbaugh AL; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Guo L; Center for Translational Cancer Research, Institute of Bioscience and Technology Texas A&M Health Science Center, Houston, TX, USA., Cai S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shao J; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhou X; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhang X; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jeter-Jones S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Fu C; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Qi Y; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Baameur Hancock F; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., White JB; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Stephan C; Center for Translational Cancer Research, Institute of Bioscience and Technology Texas A&M Health Science Center, Houston, TX, USA., Davies PJ; Center for Translational Cancer Research, Institute of Bioscience and Technology Texas A&M Health Science Center, Houston, TX, USA., Moulder S; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Eli Lilly and Company, Indianapolis, IN, USA., Symmans WF; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chang JT; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA., Piwnica-Worms H; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. hpiwnica-worms@mdanderson.org.
Jazyk: angličtina
Zdroj: NPJ breast cancer [NPJ Breast Cancer] 2024 May 27; Vol. 10 (1), pp. 37. Date of Electronic Publication: 2024 May 27.
DOI: 10.1038/s41523-024-00644-4
Abstrakt: Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.
(© 2024. The Author(s).)
Databáze: MEDLINE
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