Oncotarget

Research Papers:

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

Tanmay M. Shekhar, Mark A. Miles, Ankita Gupte, Scott Taylor, Brianna Tascone, Carl R. Walkley and Christine J. Hawkins _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:33866-33886. https://doi.org/10.18632/oncotarget.8980

Metrics: PDF 901 views  |   HTML 1127 views  |   ?  


Abstract

Tanmay M. Shekhar1, Mark A. Miles1, Ankita Gupte2, Scott Taylor2, Brianna Tascone1, Carl R. Walkley2 and Christine J. Hawkins1

1 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia

2 St. Vincent’s Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Fitzroy, Australia

Correspondence to:

Christine J. Hawkins, email:

Keywords: IAP, Smac, bone cancer, RIP1, osteosarcoma

Received: December 17, 2015 Accepted: April 16, 2016 Published: April 25, 2016

Abstract

Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 8980