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Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.
Sun, Yichen; Chen, Jianfeng; Hong, Jing Han; Xiao, Rong; Teng, Yan; Wang, Peili; Deng, Peng; Yu, Zhaoliang; Chan, Jason Yongsheng; Chai, Kelila Xin Ye; Gao, Jiuping; Wang, Yali; Pan, Lu; Liu, Lizhen; Liu, Shini; Teh, Bin Tean; Yu, Qiang; Lim, Soon Thye; Li, Wenyu; Xu, Banglao; Ong, Choon Kiat; Tan, Jing.
Afiliación
  • Sun Y; Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • Chen J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Hong JH; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Xiao R; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Teng Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Wang P; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, Guangzhou, China.
  • Deng P; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Yu Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Chan JY; Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, China.
  • Chai KXY; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • Gao J; Lymphoma Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.
  • Wang Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Pan L; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • Liu L; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, Guangzhou, China.
  • Liu S; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, Guangzhou, China.
  • Teh BT; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, Guangzhou, China.
  • Yu Q; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Lim ST; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  • Li W; Genome Institute of Singapore, A*STAR, Singapore, Singapore.
  • Xu B; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Ong CK; Genome Institute of Singapore, A*STAR, Singapore, Singapore.
  • Tan J; Director's office, National Cancer Centre Singapore, Singapore, Singapore.
Oncogene ; 43(28): 2172-2183, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38783101
ABSTRACT
Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-myc / Proteína de Unión a CREB / Aurora Quinasa A / Mutaciones Letales Sintéticas Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-myc / Proteína de Unión a CREB / Aurora Quinasa A / Mutaciones Letales Sintéticas Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido