Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN‐amplified neuroblastoma. Issue 7 (16th March 2020)

• Record Type: Journal Article
• Authors: Tee, Andrew E.; Ciampa, Olivia C.; Wong, Matthew; Fletcher, Jamie I.; Kamili, Alvin; Chen, Jingwei; Ho, Nicholas; Sun, Yuting; Carter, Daniel R.; Cheung, Belamy B.; Marshall, Glenn M.; Liu, Pei Y.; Liu, Tao
• Is Part Of: International journal of cancer. Volume 147:Issue 7(2020)
• Page Start: 1928
• Page End: 1938
• Publication Date: 2020-03-16
• Subjects: neuroblastoma -- N‐Myc -- CDK7 -- THZ1 -- tyrosine kinase inhibitors -- PNUTS; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32936
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Patients with neuroblastoma due to MYCN oncogene amplification and consequent N‐Myc oncoprotein overexpression have very poor prognosis. The cyclin‐dependent kinase 7 (CDK7)/super‐enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c‐Myc protein and suppresses c‐Myc protein degradation. Here we screened the U.S. Food and Drug Administration‐Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN ‐amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N‐Myc protein but not N‐Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N‐Myc protein but not mRNA expression and decreased MYCN ‐amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients, our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients. Abstract : What's new? Neuroblastoma caused by MYCN oncogene amplification has a very poor prognosis. The CDK7 inhibitor THZ1 clamps down on MYCN expression and halts proliferation, but doesn't kill cancer cells. Here, the authors searched for a drug that could work synergistically with THZ1. They found that tyrosine kinase inhibitors as a class work well combined with THZ1. In particular, ponatinib, lapatinib, and nilotinib showed synergistic anticancer effects with THZ1, inducing apoptosis in MYCN‐amplified neuroblastoma cells, but not normal ones. These TKIs act by blocking PNUTS gene expression. PNUTS boosts N‐Myc expression, and eliminating PNUTS inhibits neuroblastoma cell growth and induces apoptosis.