Abstract P254: Transcriptional effects in C26 tumor highlight mechanistic aspects of a novel dual MEK inhibitor, IMM-1-104

Abstract

Abstract We developed a novel dual MEK inhibitor, IMM-1-104, that showed 94% tumor growth inhibition (TGI) in the syngeneic C26 mouse model through 10 days at 150 mg/kg (mpk) BID, with only 3.8% tumor-adjusted body weight loss (BWL) through 24 days. The mechanism differs from that of standard MEK inhibitors (MEKi), and leverages signaling dynamics to decouple efficacy and toxicity. IMM-1-104 achieves deep cyclic inhibition of the pathway rather than constant blockade, and prevents the RAF1 (CRAF) bypass which has hampered standard MEKi. In this study, we examined the transcriptional effects of IMM-1-104 in the C26 model via RNA sequencing. These observations confirmed the pattern of deep cyclic inhibition, demonstrating strong MAPK pathway inhibition in tumor 2h after treatment, and near complete release 12h following treatment. This pattern was observed both after the initial dose as well as following chronic BID dosing (18 days), indicating that deep cyclic inhibition was sustainable across chronic dosing. Filtering the transcriptional signatures to examine effects that followed the pattern of deep cyclic inhibition (strong effect at 2h and release at 12h) revealed effects on mitochondrial and metabolism genes. These genes included Hk2, which was downregulated more than 2-fold after 2h of treatment with 100 mpk IMM-1-104 both after the initial dose and following chronic BID dosing. The effect on Hk2 occurred in tumor but not in muscle tissue from the same mice. These results were independent of adaptive immunity, as they were also observed in nude mice. Top transcriptional effects of IMM-1-104 treatment in tumor also included an increase in expression of Wnt pathway genes at 2h, following either a single dose or chronic BID dosing, at both 25 and 100 mpk. This increase was also observed at 12h following the 100 mpk dose. Activation of Wnt signaling in CRC tumors has previously been reported with standard MEK inhibitors. The transcriptional profile of IMM-1-104 in the C26 model highlighted key aspects of its mechanism related to signaling dynamics, which helps explain its ability to achieve high TGI and tolerability. The profile also highlighted aspects shared with standard MEKi that could shed light on potential resistance pathways. Citation Format: Sarah E. Kolitz, Kevin D. Fowler, Peter J. King, Benjamin J. Zeskind, Brett M. Hall. Transcriptional effects in C26 tumor highlight mechanistic aspects of a novel dual MEK inhibitor, IMM-1-104 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P254.