Abstract 6387: Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors
Authors: Joshua Lange, Salvador Garcia, Evan Holmes, AnneMarie Pferdekamper, Ben Norman, Auzon Steffy, Joshua Plum, Nicholas Catalano, Cory DuPai, HuiYong Zhao, Elisa de Stanchina, Claire Kuelbs, Austin Christofferson, Ardalan Ardeshiri, Edison Tse, Frederick Derheimer, Joan Chen, Debbie Liao, Ryan Hansen, Rona Yaeger, Sudhir Chowdhry, Christian Hassig
Journal: Cancer Research (2025)

Abstract KRAS targeted inhibitors have shown promising clinical data in multiple recalcitrant cancers with activating KRAS mutations. The mutant-specific, pan, and multi-RAS targeting landscape is rapidly evolving; however, both intrinsic and acquired resistance to these therapies remain a significant clinical challenge. Mechanisms of acquired resistance to KRAS targeted inhibitors include high copy number amplification of KRAS and/or MAPK-pathway genes, activation of alternative oncogenic pathways, and secondary mutations in RAS-family members. In KRAS driven cancers, estimated to represent more than 15% of all solid tumors, DNA synthesis is uniquely dependent on the de novo synthesis of deoxyribonucleotide triphosphates (dNTPs), which depends on the enzyme ribonucleotide reductase (RNR). We developed an oral, potent, and selective small molecule inhibitor of RNR, BBI-825, that we have previously shown to preclinically prevent amplification mediated resistance to KRASG12C inhibitor adagrasib, and which is currently in clinical development as part of the STARMAP (Study Treating Acquired Resistance; MAPK Amplifications) Phase 1/2 trial, including KRASG12C inhibitor resistant tumors (NCT06299761). In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models. We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Across the models tested, BBI-825 demonstrated a consistent ability to prevent or delay acquired resistance to mutant-specific and multi-RAS targeting. We found that combinational activity of BBI-825 and RAS targeting was independent of the mode of acquired resistance being driven by genetic or non-genetic mechanisms. BBI-825 was found to abrogate increases of KRAS, RAF1, and MYC copy number in models where acquired resistance to RAS targeting was mediated via amplification of these genes. BBI-825 also showed combinational activity in RAS-targeting resistant cell lines where resistance was driven by non-genetic signaling alterations. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response. Citation Format: Joshua Lange, Salvador Garcia, Evan Holmes, AnneMarie Pferdekamper, Ben Norman, Auzon Steffy, Joshua Plum, Nicholas Catalano, Cory DuPai, HuiYong Zhao, Elisa de Stanchina, Claire Kuelbs, Austin Christofferson, Ardalan Ardeshiri, Edison Tse, Frederick Derheimer, Joan Chen, Debbie Liao, Ryan Hansen, Rona Yaeger, Sudhir Chowdhry, Christian Hassig. Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6387.