RESUMO
To address the unmet need for effective biomarker-driven targeted therapy for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, we conducted a high-throughput drug screen using 1122 compounds in 13 HPV-positive and 11 matched HPV-negative cell lines. The most effective drug classes were inhibitors of polo-like kinase, proteasomes, histone deacetylase, and Aurora kinases. Treatment with a pan-Aurora inhibitor, danusertib, led to G2M arrest and apoptosis in vitro. Furthermore, danusertib decreased tumor size compared with controls in patient derived xenograft models of HNSCC. To identify biomarkers predicting response, we determined associations between mutations and drug sensitivity. Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora kinase inhibitor-induced apoptosis. We identified Aurora kinase inhibitors as effective and understudied drugs in HNSCC and CESC. This is the first published study to demonstrate that mutations in KMT2D, which are common in many cancers, correlate with drug sensitivity in two independent datasets.
Assuntos
Aurora Quinase A/antagonistas & inibidores , Carcinoma de Células Escamosas/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas de Neoplasias/genética , Infecções por Papillomavirus/genética , Animais , Apoptose , Área Sob a Curva , Benzamidas/farmacologia , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/virologia , Ciclo Celular , Linhagem Celular , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Papillomaviridae , Infecções por Papillomavirus/tratamento farmacológico , Farmacogenética , Pirazóis/farmacologia , Neoplasias do Colo do ÚteroRESUMO
A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 µM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.