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Updated: Mar 22, 2026
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
Tanmay M Shekhar1, Mark A Miles1, Ankita Gupte2
1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
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.
Insights
New IAP antagonists show promise in treating osteosarcoma, a bone cancer with poor outcomes. These Smac mimetics sensitize cancer cells to TNFα, offering a potentially safer alternative to chemotherapy with no mutagenic activity.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Osteosarcoma outcomes have stagnated for decades, with limited survival rates for metastatic disease.
- Current DNA-damaging chemotherapy poses risks like cardiotoxicity and secondary cancers.
- Safer, more effective osteosarcoma treatments are urgently needed.
Purpose of the Study:
- To investigate the efficacy of IAP antagonists (Smac mimetics) against osteosarcoma.
- To determine if these agents can sensitize osteosarcoma cells to tumor necrosis factor-alpha (TNFα).
- To assess the safety profile, including mutagenicity, of IAP antagonists.
Main Methods:
- Utilized mouse models of osteosarcoma lacking p53 and Rb expression.
- Tested IAP antagonists (SM-164, GDC-0152, LCL161) targeting XIAP and cIAPs.
- Assessed sensitization to TNFα and TRAIL, and correlated sensitivity with RIPK1 and RIPK3 expression.
Main Results:
- IAP antagonists sensitized most osteosarcoma cells to low levels of TNFα, but not TRAIL.
- Sensitivity was linked to RIPK1 expression levels and activity.
- RIPK3 expression varied but was not essential for TNFα sensitization.
- Tested IAP antagonists demonstrated no mutagenic activity.
Conclusions:
- IAP antagonists are potential therapeutic agents for osteosarcoma.
- Treatment efficacy may be enhanced in tumors with high RIPK1 and TNFα levels.
- These drugs offer a safer alternative, potentially avoiding therapy-induced cancers.
