Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants. (1st September 2018)

• Record Type: Journal Article
• Authors: Kalu, Nene N.; Mazumdar, Tuhina; Peng, Shaohua; Tong, Pan; Shen, Li; Wang, Jing; Banerjee, Upasana; Myers, Jeffrey N.; Pickering, Curtis R.; Brunell, David; Stephan, Clifford C.; Johnson, Faye M.
• Is Part Of: Cancer letters. Volume 431(2018)
• Page Start: 64
• Page End: 72
• Publication Date: 2018-09-01
• Subjects: Lysine methyltransferase 2D -- MLL2 -- Head and neck squamous cell carcinoma -- Cervical cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.05.029
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: We conducted the largest drug screen to date in HPV-positive cancers and identified Aurora kinase inhibitors as effective drugs. Aurora kinase inhibition led to G2M arrest and apoptosis in vitro and decreased tumor size in vivo in a patient derived xenograft model. KMT2D (MLL2) mutations may be a suitable biomarker for patient selection since they correlated with drug sensitivity in two independent datasets and knockdown of KMT2D led to increased drug-induced apoptosis. Truncating KMT2D (MLL2) mutations occur in many cancers including bladder (23%), HNSCC (12%), CESC (9%), and squamous lung carcinoma (11%). Given that KMT2D mutations are common and Aurora kinase inhibitors are in clinical development, our results have potential for rapid clinical translation.