Abstract B023: The next-generation farnesyltransferase inhibitor KO-2806 constrains compensatory signaling reactivation to deepen responses to KRASG12D inhibition
Authors: Smith Alison , Patel Hetika , Chan Stacia , Burrows Francis , Malik Shivani 
Published: December 2023

The landmark approval of KRASG12C inhibitors toppled the decades-held notion that KRAS was undruggable, fueling the design and development of small molecules targeting other oncogenic KRAS mutants, including the most prevalent, KRASG12D. MRTX1133 is the first KRASG12D-selective inhibitor to reach the clinic, providing a much-needed therapeutic option for patients with KRASG12D-mutant tumors. Nevertheless, both preclinical MRTX1133 data and early clinical results from KRASG12C inhibitor trials suggest that responses to KRASG12D inhibition will vary widely, at least in part due to incomplete and/or transient inhibition of MAPK and mTOR signaling. We previously demonstrated that farnesyltransferase inhibitors (FTIs) can prevent adaptive resistance to PI3K inhibition by blunting compensatory reactivation of these signaling nodes. We therefore hypothesized that farnesyltransferase inhibition may similarly enhance the antitumor activity of MRTX1133 through synergistic blockade of mitogenic and survival signaling. In this study, we leveraged a panel of in vivo cell line (CDX) and patient-derived xenograft (PDX) models, in parallel with in vitro mechanistic studies, to assess the efficacy of combined KO-2806, a FTI, and MRTX1133, in controlling KRASG12D-mutant tumor growth.   KO-2806 is a next-generation FTI with increased potency and improved pharmacokinetic properties relative to earlier FTI candidates and is poised to enter a first-in-human clinical trial. Given that reactivation of phospho-ERK and phospho-S6 is linked to diminished response to MRTX1133, we first probed the impact of KO-2806 on cell signaling in vitro. In KRASG12D mutant cell lines, MRTX1133 transiently inhibited both ERK and mTOR, as evidenced by decreased ERK, p90 RSK, p70 S6K, S6, and 4EBP1 phosphorylation. However, phosphorylation of these proteins rebounded partially within one day and completely by 48 hours post treatment. In contrast, when cells were co-exposed to MRTX1133 and KO-2806, robust inhibition of these pathways was maintained at 48 hours and corresponded with greater induction of apoptosis (PARP and caspase cleavage) and cell cycle arrest (ablation of Rb phosphorylation) compared to MRTX1133. These results are consistent with prior reports suggesting that durable MAPK and mTOR inhibition is required for optimal response to KRAS inhibitors.  The mechanistic synergy we observed in vitro provided a strong rationale for evaluating combined MRTX1133 and KO-2806 in vivo. Across a panel of KRASG12D-mutant CDX and PDX solid tumor models, the MRTX1133/KO-2806 doublet led to deeper tumor growth inhibition compared to the single agents while remaining well tolerated in mice. We posit that KO-2806 augments the MAPK-mTOR inhibitory effects of MRTX1133 by blocking compensatory pathway reactivation, resulting in superior antitumor efficacy of the combination without amplifying toxicity. Based upon these results, combined farnesyltransferase and KRASG12D inhibition represents a promising therapeutic strategy for the treatment of KRASG12D0-mutant solid tumors.

Citation Format: Alison Smith, Hetika Patel, Stacia Chan, Francis Burrows, Shivani Malik. The next-generation farnesyltransferase inhibitor KO-2806 constrains compensatory signaling reactivation to deepen responses to KRASG12D inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B023.