Osteosarcoma cells depend on MCL-1 for survival, and osteosarcoma metastases respond to MCL-1 antagonism plus regorafenib in vivo

Ji, Y; Harris, MA; Newton, LM; Harris, TJ; Fairlie, WD; Lee, EF; Hawkins, CJ

Author(s): Ji, Y; Harris, MA; Newton, LM; Harris, TJ; Fairlie, WD; Lee, EF; Hawkins, CJ;
Details: Publication Year 2024-11-04,Volume 24,Issue #1,Page 1350
Journal Title: BMC Cancer
Publication Type: Research article
Abstract: Osteosarcoma is the most common form of primary bone cancer, which primarily afflicts children and adolescents. Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s. However, osteosarcoma survival rates have remained stagnant for several decades. Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib. BCL-2 and its close relatives enforce cellular survival and have been implicated in the development and progression of various cancer types. BH3-mimetics antagonize pro-survival members of the BCL-2 family to directly stimulate apoptosis. These drugs have been proven to be efficacious in other cancer types, but their use in osteosarcoma has been relatively unexplored to date. We investigated the potential efficacy of BH3-mimetics against osteosarcoma cells in vitro and examined their cooperation with regorafenib in vivo. We demonstrated that osteosarcoma cell lines could be killed through inhibition of MCL-1 combined with BCL-2 or BCL-x(L) antagonism. Inhibition of MCL-1 also sensitized osteosarcoma cells to killing by second-line osteosarcoma treatments, particularly regorafenib. Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes.
Publisher: BioMed Central
Keywords: *Osteosarcoma/drug therapy/pathology/mortality; *Pyridines/pharmacology/therapeutic use; *Phenylurea Compounds/pharmacology/therapeutic use; Humans; *Myeloid Cell Leukemia Sequence 1 Protein/metabolism/antagonists & inhibitors; Animals; Mice; Cell Line, Tumor; *Bone Neoplasms/drug therapy/pathology/mortality; *Xenograft Model Antitumor Assays; Apoptosis/drug effects; Cell Survival/drug effects; Lung Neoplasms/drug therapy/pathology/mortality; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use; BCL-xL; BH3-mimetic; Kinase inhibitor; Mcl-1; Osteosarcoma; Regorafenib; S63845; Sarcoma
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1186/s12885-024-13088-7
Open Access at Publisher's Site: https://doi.org/10.1186/s12885-024-13088-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-11-28 05:45:59

Last Modified: 2024-11-28 06:29:14