Article
作者: Yang, Jennifer ; Ward, Antonio B ; Berry, Kristy L ; Smith, Forrest T ; Buchsbaum, Donald J. ; El-Rayes, Bassel F. ; Boyd, Michael R. ; Wang, Junwei ; Smith, Forrest ; Yoon, Karina J ; Piazza, Gary A. ; Fleten, Karrianne G ; Yoon, Karina J. ; Berry, Kristy L. ; Manne, Upender ; Huang, Chung-Hui ; Bae, Sejong ; Fleten, Karianne G ; Mattox, Tyler E ; Mitra, Amit K ; Ward, Antonio B. ; Bandi, Dhana Sekhar Reddy ; Abdelkarim, Hazem ; Foote, Jeremy B. ; Nagaraju, Ganji P ; Babic, Ivan ; Fleten, Karrianne G. ; Gaponenko, Vadim ; Nurmemmedov, Elmar ; Keeton, Adam B. ; Mitra, Amit K. ; Ramirez-Alcantara, Veronica ; Nurmmedov, Elmar ; Flatmark, Kjersti ; Gorman, Gregory S ; Piazza, Gary A ; Gorman, Gregory S. ; Wang, Chung-Hui ; Carstens, Julienne L ; Holmes, Thomas ; Carstens, Julienne L. ; Holmes, Thomas W ; Chen, Xi ; Valiyaveettil, Jacob ; Alcantara, Veronica R ; Nagaraju, Ganji Purnachandra ; Foote, Jeremy B ; El-Rayes, Bassel F ; Mattox, Tyler E. ; Sarvesh, Sujith ; Boyd, Michael R ; Hardy, Cherlene ; Buchsbaum, Donald J ; Zhou, Gang ; Foote, Jeremy ; Maxuitenko, Yulia ; Keeton, Adam B ; Maxuitenko, Yulia Y.
ABSTRACTHere, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWTcancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWTcancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWTand normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impactin vivoantitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers.SIGNIFICANCEADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.
