Investigating the Downstream Oncogenic Consequences and Therapeutic Susceptibilities Caused by Loss of ARID1A in Neuroblastoma
Abstract
Neuroblastoma (NB) accounts for 15% of pediatric cancer deaths, and more than 50% of children with high-risk NB do not survive. Treatment for high-risk NB, the most common cancer of infancy, is an intensive multimodal treatment of surgery, high-dose radiation, high-dose chemotherapy, immunotherapy, and, to rescue from treatment-related damage to the blood system, a bone marrow transplant. Despite this intensive treatment regimen, more than 60% of high-risk NB patients will succumb to disease within 5 years and survivors are at a higher risk for secondary cancers as well as other lifelong morbidities. Children with high-risk NBs have large regions of their DNA containing hundreds of genes missing or duplicated. Without knowing which genes in those regions drive NB, it is difficult to develop new targeted therapies. Using our previous Peer Reviewed Cancer Research Program (PRCRP) funding, we created a robust and tractable system for screening candidate genes by investigating if they can turn the cells that NB arises from into NB. Using this system, we determined that loss of the gene ARID1A is important in helping N-Myc cause NB. N-Myc is one of the few genes known to cause NB and it is found amplified in 40% of high-risk NB. The region where ARID1A is located, 1p36, is lost in 70% of N-Myc amplified NB, indicating that these two events work together. In fact, NB researchers have spent decades trying to identify the relevant 1p36 gene that cooperates with amplified N-Myc, making our finding a significant discovery for the field. Scientists have recently become aware of the importance of ARID1A, and the SWI/SNF complex that it is part of, in cancer. Greater than 20% of cancers have ARID1A or SWI/SNF subunit mutations, including many of the Fiscal Year 2017 PRCRP cancers such as liver cancers (40%), stomach cancers (36%), melanomas (34%), pancreatic cancers (23%), glioblastomas (14%) and medulloblastomas (10%). Cancers with mutations in ARID1A and SWI/SNF represent a significant medical burden to military personnel, Veterans, and their beneficiaries yet the role of ARID1A in cancer is significantly understudied. N-Myc and related genes are part of the Myc family of oncogenes. This family of oncogenes drives cell proliferation and DNA replication, the process of making copies of the entire genetic material of the cell. The high rates of DNA replication driven by N-Myc can cause replication stress and DNA damage. Cells have a process to handle DNA damage called the DNA damage response (DDR). ARID1A and the SWF/SNF complex provide control for regulating genes expression, but new evidence suggests ARID1A also helps repair damage by participating in the DDR. In principle, if there are low levels of DNA damage, the DDR repairs the cell while sending signals telling the cell to survive. If damage is too extreme, the DDR tells the cell to die or to never replicate again. We hypothesize that loss of ARID1A causes the cells to choose survival over death at a higher threshold of damage. This would cause cells to tolerate greater damage from N-Myc driven cell proliferation, explaining why the region containing ARID1A is often lost when N-Myc is amplified. In the first part of the grant, we will test if ARID1A alters the DDR when N-Myc is overexpressed. In other cancers, it has been demonstrated that loss of function from small mutations in ARID1A make the cancer susceptible to inhibitors of the DDR. Based on the proposed role of ARID1A in DDR, the underlying concept behind this is that loss of some DNA damage sensing caused by loss of ARID1A allows oncogenes like N-Myc to more easily drive proliferation without causing death. However, if sensing of DNA damage is too impaired by layering inhibitors of DDR on top of loss of ARID1A, it is catastrophic to the cells because insufficient repair is happening. In the second part of the grant, we will screen DDR inhibitors against an engineered panel of cell lines to he
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810477
Entities
People
- Kevin W Freeman
Organizations
- United States Army
- University of Tennessee Health Science Center