| Autor: |
Marina Konopleva, Timothy Yap, Naval Daver, Mikhila Mahendra, Jixiang Zhang, Carlos Kamiya-Matsuoka, Funda Meric-Bernstam, Hagop Kantarjian, Farhad Ravandi, Meghan Collins, Maria Di Francesco, Ecaterina Dumbrava, Siqing Fu, Sisi Gao, Jason Gay, Sonal Gera, Jing Han, David Hong, Elias Jabbour, Zhenlin Ju, Daniel Karp, Alessia Lodi, Jennifer Molina, Natalia Baran, Aung Naing, Maro Ohanian, Shubham Pant, Naveen Pemmaraju, Prithviraj Bose, Sarina A. Piha-Paul, Jordi Rodon, Carolina Salguero, Koji Sasaki, Anand Singh, Vivek Subbiah, Apostolia M. Tsimberidou, Quanyun Xu, Musa Yilmaz, Qi Zhang, Christopher Bristow, Meenakshi Bhattacharjee, Stefano Tiziani, Timothy Heffernan, Christopher Vellano, Philip Jones, Cobi Heijnen, Annemieke Kavelaars, Joseph Marszalek |
| Rok vydání: |
2022 |
| Popis: |
While targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, patient benefit with OXPHOS inhibitors in the clinic has yet to be achieved. Based on promising preclinical data, we advanced IACS-010759, a highly potent and selective small-molecule inhibitor of mitochondrial complex I, into two phase I trials in patients with acute myeloid leukemia (NCT02882321) or advanced solid tumors (NCT03291938). Clinical findings revealed that IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities that included elevated blood lactate and neurotoxicity, obstructing efforts to maintain target plasma exposure. Consequently, only modest on-target inhibition and limited antitumor activity were observed. Follow-up reverse translational studies uncovered that IACS-010759 reduced oxygen consumption rates in neurons and damaged myelin. Further, IACS-010759-treated mice displayed behaviors indictive of neuropathy, which were minimized with the co-administration of a histone deacetylase 6 inhibitor. Our findings urge caution in the continued development of complex I inhibitors as antitumor agents. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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