Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Irène Baccelli, Yves Gareau, Bernhard Lehnertz, Stéphane Gingras, Jean-François Spinella, Sophie Corneau, Nadine Mayotte, Simon Girard, Mélanie Frechette, Valérie Blouin-Chagnon, Koryne Leveillé, Isabel Boivin, Tara MacRae, Jana Krosl, Clarisse Thiollier, Vincent-Philippe Lavallée, Evgeny Kanshin, Thierry Bertomeu, Jasmin Coulombe-Huntington, Corinne St-DenisSummaryTo identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.
Conclusion RE may mitigate tumor growth and tumor malignancy parameters such as lower histopathological grade, assuming less nuclear pleomorphism and mitotic cells, smaller viable tumor area, and decreased tumor cell proliferation in both adenocarcinomas. In addition, RE induced tumor vascularization.
Authors: Nisker J Abstract Dissolution of Canada's single-tiered health system is now before the Supreme Court of British Columbia and will soon be before the Supreme Court of Canada. If our Supreme Court justices are persuaded to dissolve the Canada Health Act, financially advantaged Canadians will be permitted to purchase privileged access to physicians, diagnostic tests, and surgical facilities. This queue jumping will diminish access for the socioeconomically disadvantaged, among whom women are overrepresented, including women living with disabilities, women of Indigenous heritage, and women who have recently i...
This workshop focuses on endpoints for the development of systemic neoadjuvant therapies for the treatment of muscle-invasive bladder cancer.
Duke University researchers found dangerous levels of pulegone in three mint-flavored e-cigarette liquids and warned that the FDA needs to regulate the chemical linked to cancers.
A cancer-causing compound banned by U.S. regulators last year as a food additive has been found at potentially dangerous levels in mint and menthol flavored e-cigarette liquids and smokeless tobacco products, researchers said on Monday.