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

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.

Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer

“…These studies demonstrated a synergistic anti-proliferative effect, and an enhancement in apoptosis and decreases in p-CDC2 in AZD1775-treated ovarian cancer cells that was maintained in the combination. Additionally, AZD1775 in combination with the Aurora Kinase A inhibitor, alisertib, also demonstrated an enhanced anti-tumor effect with increases in apoptosis and γ-H2AX in head and neck cancers [22]. These data suggest that combination therapies with AZD1775 and chemotherapy or other targeted agents are viable options for treatment for various tumor types.…”

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

“…For example, CDK4/6 kinase inhibitors are activated by association with cyclins D and E, are required for progression through G1 and S phase, have established efficacy against breast cancer, and are currently under evaluation for HNSCC [7][8][9]. Other kinases that have been evaluated as targets in preclinical or clinical studies in HNSCC include Aurora A (AURKA) [10][11][12] and Polo-like kinase 1 (PLK1) [13], required for entry into and progression through M phase. Mechanistically, CDK1 activation proximally governs entry into M phase; CDK1 activation depends on the removal of an inhibitory phosphorylation of Y 15 , which is mediated by the CDC25 family phosphatases.…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…Evaluated by γ‐H2A.X expression, OSCC cells had lower DSBs frequencies and slower repair rate (Jessri, Dalley, & Farah, ) and oridonin induced apoptosis via the augmentation of γ‐H2A.X in response to DNA damage (Yang, Shin, et al, ). Elevated Aurora kinase (ARK) AURKA indicated worse survival in patients with p16‐negative HNSCC (Lee et al, ). Concomitant AURKA overexpression plus epidermal growth factor receptor (EGFR/ERBB) elevation depicted a risk HNSCC group with adverse clinical outcomes (Hoellein et al, ).…”

“…In mutated tumor‐suppressor p53 HNSCC cells, ARKA inhibitor alisertib induced spindle defects, G2/M arrest, CDK1 inhibitory phosphorylation, and cytostasis (Lee et al, ). Alisertib also caused PARP cleavage and anti‐apoptotic Bcl‐2 family Mcl‐1 degradation in E7‐expressing HNSCC cells.…”

“…Synergistic inhibition of tumor growth and improved OS were observed when Wee1 inhibitor adavosertib was added to ARKA inactivation via alisertib (Lee et al, ).…”