NRF2 disruption by rocaglate translation inhibitors sensitizes tumors to induction of ferroptosis and killing by CAR-T cells (EORTC-NCI-AACR 2024) - Sep 8, 2024 - Abstract #226; PB214; Pres time: Oct 24, 2024; 09:00 AM - 05:30 PM; Location: Exhibition Hall; "We assessed the combination of zotatifin and the optimized ferroptosis-inducing compound imidazole ketone erastin (IKE) in vivo against lymphoma xenografts. Zotatifin synergizes strongly with IKE and multiple other ferroptosis inducers in vitro. We reveal NRF2 can be indirectly targeted through disruption of its translation by eIF4A inhibition with rocaglates, including the clinical compound zotatifin. NRF2 loss causes profound sensitization to ferroptosis-inducing drugs and killing by cytotoxic T cells. These results inform clinical strategies to enhance activities of investigational ferroptosis inducers and approved CAR-T cells."
CAR T-Cell Therapy • IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin's Lymphoma • Oncology • Solid Tumor • EIF4A1 • EIF4A2 • IFNG • NFE2L2
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P. Manara 1; A.D. Newsam 1; V. Venkatarame Gowda Saralamma 1; M.V. Russo 2; T.A. Cunningham 1; K. Hoffman 3; A. Youssfi Alaoui 1; P.A. Younes 4; A. Mirauti 1; O.B. Lightfuss 1; D. Bilbao Cortes 2; J.H. Schatz 1
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