한빛사 논문
Jong Woo Lee1, Janaki Parameswaran1+, Teresa Sandoval-Schaefer1, Kyung Jin Eoh1, Dong-hua Yang2** , Fang Zhu3, Ranee Mehra4^, Roshan Sharma1, Stephen G. Gaffney5, Elizabeth B. Perry5, Jeffrey P. Townsend5, Ilya G. Serebriiskii6, Erica A. Golemis6, Natalia Issaeva7, Wendell G. Yarbrough7,8, Ja Seok Koo1, and Barbara Burtness1*
1 Section of Medical Oncology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, CT,
2 Biosample Repository, Fox Chase Cancer Center, Philadelphia PA
3 Department of Biostatistics, Fox Chase Cancer Center, Philadelphia PA
4 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia PA,
5 Department of Biostatistics, Yale University School of Public Health, New Haven, CT
6 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia PA
7 Section of Otolaryngology, Department of Surgery, Yale University School of Medicine
8 Department of Pathology, Yale University School of Medicine
*Corresponding Author: Barbara Burtness, MD, Department of Medicine, Section of Medical Oncology, Yale University School of Medicine and Yale Cancer Center. 333 Cedar Street, New Haven, CT 06520-8023.
Abstract
Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition.
Experimental Design: AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using in vitro and in vivo HNSCC models.
Results: Elevated nuclear AURKA correlated with worse survival among p16(-) HNSCC patients. Alisertib caused spindle defects, G2/M arrest and inhibitory CDK1 phosphorylation, and cytostasis in TP53 mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared to either vehicle or single agent treatment.
Conclusions: Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in in vitro and in vivo HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for TP53-mutated cancers.
Key words: WEE1, Aurora Kinase A, alisertib, adavosertib, HNSCC
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기