Jim Evans

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product–inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS G12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS G12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS G12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

Agricultural media merit increased attention in addressing dynamic changes in safety aspects of one of the nation's most hazardous industries. Changes in farming, such as larger-scale, new "niche" enterprises and new technologies, bring new forms of risk to the safety of those who live and work on farms and ranches. At the same time, traditional agricultural media--commercial firms that publish farm periodicals and commercial radio/television stations and networks that provide farm programming--are changing dramatically. In the face of media convergence, these enterprises provide an increasing menu of agricultural information services delivered by print, radio, and television, plus a host of new electronic media. This review of literature addressed the role and importance of commercial agricultural media in the United States, the scope and pattern of their safety coverage, and the opportunities they represent. The review involved searches of 14 bibliographic databases, as well as reference lists of relevant studies and contacts with farm safety experts. Analysis of 122 documents suggested that limited focus has been directed to the role of commercial agricultural media in safety decisions on US farms. Findings revealed that they continue to serve an efficient, early-stage role in creating awareness and interest, providing information, forming attitudes, and stirring consideration of farm safety. Potentials are seen as expanding through the interactive features of social media and other new services offered by these media firms. Findings also identified research needs, 100 farm safety topics for reporting, and opportunities for strengthening safety coverage by commercial agricultural media.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is driven by oncogenic RAS mutations in >90% of cases. Daraxonrasib (RMC-6236) is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor with broad-spectrum activity against oncogenic mutant and wild-type variants of N, H and KRAS. We reported encouraging efficacy of daraxonrasib at tolerated dose levels of 160 to 300 mg daily as of a data cutoff of 23 Jul 2024 in patients with previously treated, RAS mutant metastatic PDAC, with median progression free survival (PFS) of 7.6 months (95% CI, 5.9 to 11.1) and overall survival (OS), 14.5 months (95% CI, 8.8 to not evaluable). Here, we report preclinical and clinical evidence for potential mechanisms of acquired resistance following monotherapy treatment with daraxonrasib in PDAC. Genomic alterations in baseline and end of treatment ctDNA were compared in 26 patients with PFS>3 months on daraxonrasib. Putative genomic mechanisms of resistance to daraxonrasib were found in 62% (16/26), including acquired amplifications of KRAS in 35% (9/26) of patients. No acquired oncogenic secondary KRAS mutations were observed, distinct from resistance profiles reported for mutant-selective KRAS G12C(OFF) inhibitors, and consistent with the broad RAS inhibitory activity of daraxonrasib. Acquired alterations were observed in RAF (4; 15%), RTKs (3; 12%), PI3K pathway genes (2; 8%), and MYC (1; 4%) of patients. Multiple acquired alterations were detected in ctDNA from 6 patients (23%). Consistent with our clinical findings, alterations driving daraxonrasib resistance in preclinical models in vitro and in vivo included KRAS amplification, alterations in RAF and upregulation of RTKs. We have previously reported acquired Myc amplification as a potential mechanism of resistance to RAS(ON) multi-selective inhibition in preclinical models. Together, our clinical and preclinical data converge on a set of resistance mechanisms that drive genomic reactivation of RAS pathway signaling in PDAC following the selective pressure exerted by daraxonrasib monotherapy, discernible from those reported for mutant-selective KRAS G12C(OFF) inhibitors. We hypothesize that increased therapeutic pressure on RAS signaling, via an increase in total RAS target occupancy, could address these resistance mechanisms. We demonstrate that the combination of daraxonrasib with a mutant-selective RAS(ON) inhibitor (either the RAS(ON) G12C mutant selective inhibitor elironrasib (RMC-6291), or the RAS(ON) G12D mutant selective inhibitor zoldonrasib (RMC-9805)) drove combinatorial benefit and forestalled monotherapy resistance in a series of preclinical models. The RAS(ON) inhibitor doublets of elironrasib or zoldonrasib with daraxonrasib are currently being evaluated in patients with tumors harboring RAS G12C and RAS G12D, respectively. Citation Format: Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick P. Lai, Alexander Starodub, Alexander Spira, Salman R. Punekar, Ignacio Garrido-Laguna, Wungki Park, David S. Hong, Anirban Maitra, David Sommerhalder, Minal Barve, Meredith Pelster, Harika Gundlapalli, Vidya Seshadri, Shurui Cai, Mark Labrecque, Wan-Ying Hsieh, Sean Bredeson, Jim Evans, Brett Garrick, Yevgeniy Gindin, Cristina Blaj, Marie Menard, Lingyan Jiang, Elsa Quintana, Matthew Holderfield, Aparna Hegde, Jingjing Jiang, Zeena Salman, W Clay Gustafson, Jacqueline A. Smith, Brian Wolpin, Ida Aronchik, Kevin K. Lin, Andrew J. Aguirre, Mallika Singh. Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB281.