Supplementary Figure S5 from Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck

Lee, Jong Woo; Parameswaran, Janaki; Sandoval-Schaefer, Teresa; Eoh, Kyung Jin; Yang, Dong-hua; Zhu, Fang; Mehra, Ranee; Sharma, Roshan; Gaffney, Stephen G.; Perry, Elizabeth B.; Townsend, Jeffrey P.; Serebriiskii, Ilya G.; Golemis, Erica A.; Issaeva, Natalia; Yarbrough, Wendell G.; Koo, Ja Seok; Burtness, Barbara

doi:10.1158/1078-0432.22470465.v1

10780432ccr180440-sup-196707_2_supp_5323286_pmfllh.pdf (63.2 kB)

Supplementary Figure S5 from Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck

journal contribution

posted on 2023-03-31, 20:49 authored by Jong Woo Lee, Janaki Parameswaran, Teresa Sandoval-Schaefer, Kyung Jin Eoh, Dong-hua Yang, Fang Zhu, Ranee Mehra, Roshan Sharma, Stephen G. Gaffney, Elizabeth B. Perry, Jeffrey P. Townsend, Ilya G. Serebriiskii, Erica A. Golemis, Natalia Issaeva, Wendell G. Yarbrough, Ja Seok Koo, Barbara Burtness

Supplementary Figure S5 related to Figure 5H. (A) Heat map QIF of pCDK1 expression intensity in FaDu xenograft mice treated with (a) vehicle, (b) alisertib, (c) adavosertib or (d) alisertib+adavosertib. Scores range from very low (purple) to high (yellow). Black squares represent FOVs in which QIF scores were not calculated due to presence of artifacts, lack of tumor, etc. (B) Graph depicts Mean {plus minus} SD of QIF scores of pCDK1 in nuclei in tumor. The expression of pCDK1 is significantly reduced in adavosertib and alisertib+adavosertib treated FaDu-xenografted mice. Statistical significance was determined by one-way ANOVA followed by Tukey's multiple comparisons test (****: P < 0.0001; n.s.: not significant).

History

ARTICLE ABSTRACT

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. Elevated nuclear AURKA correlated with worse survival among patients with p16(−) HNSCC. 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 with either vehicle or single-agent treatment. 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.