抑制TRIM7可阻断RTK/RAS通路驱动的肿瘤增殖，且不依赖突变，并在KRASi耐药情境下有效

Most cancer patients experiencing clinical benefit from targeted therapies in RTK-KRAS driven cancers develop acquired resistance (AR) and relapse. The mechanism of resistance in patients who initially respond to monoallelic KRAS G12C/G12D inhibitors is dominated by the accumulation of new mutations in KRAS itself, followed by mutations downstream in the MAP kinase pathway. Therapeutics that more broadly target this pathway, like the multi-KRAS isoform inhibitor daraxonrasib, offer promise in less common mutations (e.g., KRAS G12X/Q61X). However, the tolerability of KRASi combinations has been a concern, and it is unclear whether similar resistance mechanisms will arise in multi-KRASi treated patients, as has been seen in monoallelic-KRASi treated patients. To identify novel approaches for complex or resistant RTK-KRAS driven cancers, we generated a murine CRC KRAS(G12D) AR model and through transcriptional/proteomic analysis, identified the E3 ubiquitin ligase TRIM7 as a putative driver of resistance. TRIM7 is downstream in the RTK-KRAS pathway and is upregulated in KRAS mutant and MSI-high tumors, resulting in (1) aberrant cell proliferation through ubiquitination and stabilization of RACO-1 and activated cJun/AP1 transcription, and (2) dysregulated IFN responsiveness through ubiquitination and degradation of MAVS and STING. TRIM7 is not a known mutated oncogene; rather, its hyperactivation is a byproduct of increased RTK-KRAS signaling due to upstream amplifications or mutations. We developed a highly potent and selective TRIM7 small-molecule inhibitor (KT-300) and showed it directly disrupts the ubiquitination and stability of RACO-1, resulting in decreased phosphorylation of cJun and STAT3, and altered transcription of cJun/AP1 targets. KT-300 reduced ubiquitination of MAVS, resulting in MAVS accumulation, and restored STING signaling in tumor cells where STING was impaired due to TRIM7 overexpression. KT-300 induced significant TGI in a range of KRAS/NRAS mutant tumor models (G12X, G13X, and Q61X) and in cell lines with amplification or mutation of EGFR or MAP kinase. TRIM7 specificity was confirmed using inactive enantiomers, which did not induce TGI. In vivo , monotherapy KT-300 delayed the growth of human KRAS-mutant NSCLC, CRC, and PDAC tumor xenograft and PDX models. TRIM7i-induced anti-tumor activity was enhanced in combination with concurrent KRAS inhibition, and KT-300 monotherapy delayed tumor growth in mice that developed resistance and progressed on KRAS inhibitors. TRIM7 inhibition via KT-300 may offer broad, mutation-agnostic activity in RTK-KRAS driven cancers. This represents a novel “pan-RTK-KRAS pathway inhibition” strategy that could extend efficacy to complex mutational backgrounds not addressed by current KRAS inhibitors, including in patients who have developed resistance to existing RTK-KRAS targeted therapies.