The OXPHOS complex I inhibitor IACS-010759 for mantle cell and B cell lymphoma

INDICATION: Mantle cell lymphoma (MCL); B cell lymphoma

Patient sample, cell culture and mouse studies identified an OXPHOS complex I inhibitor that could help treat MCL and B cell lymphoma that are resistant to Imbruvica ibrutinib. In MCL patients, high expression of genes in multiple OXPHOS complexes, including complex I, was associated with resistance to Imbruvica. In two Imbruvica-resistant human MCL cell lines, a tool compound OXPHOS complex I inhibitor decreased proliferation compared with no treatment. In a patient-derived xenograft (PDX) mouse model of Imbruvica-resistant MCL, the compound decreased tumor growth compared with vehicle. In a second PDX mouse model of Imbruvica-resistant MCL and a PDX mouse model of Imbruvica-resistant B cell lymphoma, the compound decreased tumor growth and increased survival compared with Imbruvica. Next steps include testing the compound in a cohort of patients with Imbruvica-resistant MCL in an ongoing Phase I trial in acute myelogenous leukemia (AML) and solid tumors...