2023 World Conference on Lung Cancer (Posters)-P1.02. Co-inhibition of MEK/RTKs Pathways via Trametinib Plus Anlotinib forKRAS-Mutant NSCLC

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Researchers from Shanghai Chest Hospital and Shanghai Institute of Biochemistry and Cell Biology have investigated the therapeutic strategy for KRAS-mutant non-small cell lung cancer (NSCLC). KRAS mutation is one of the most frequent alterations in NSCLC. The study focused on the KRAS mutation subtypes KRASG12F, KRASG12D, KRASQ61H, KRASG12V, and KRASG12A.<br /><br />The researchers performed functional and mechanism analysis on KRAS-mutant NSCLC cell lines, as well as cell-derived xenografts. They used multi-omics analysis to discuss underlying targets and employed molecular biology methods to validate alterations of signaling pathways.<br /><br />The results of the study showed that co-inhibition of MEK/RTKs pathways with trametinib and anlotinib contributes to a synergistic anti-tumor efficacy in KRAS-mutant NSCLC. The combination of trametinib and anlotinib demonstrated a synergistic effect on cell lines and xenografts derived from KRAS-mutant NSCLC cells.<br /><br />The study also elucidated the molecular mechanisms of MEKi-trametinib plus RTKs inhibitor-anlotinib in KRAS-mutant NSCLC at the in vitro and in vivo levels. The combination of anlotinib and trametinib was found to potentially inhibit cell cycle signaling, leading to a synergistic anti-tumor efficacy.<br /><br />Additionally, the researchers found that inhibition of IGFBP2 enhances the inhibitory efficacy of MEK inhibitor for KRAS-mutated NSCLC. Remodeling the IGFBP2/c-MYC pathway potentially reverses adaptive drug resistance in these cancer cells. The RTKs inhibitor anlotinib also blocks the MEKi-trametinib-induced IGFBP2/c-MYC pathway remodeling.<br /><br />In conclusion, this study provides preclinical evidence of the novel combination of anlotinib and trametinib as a therapeutic strategy against KRAS-mutant NSCLC. The study highlights the importance of co-inhibition of MEK and RTKs pathways in inhibiting the growth of KRAS-mutated NSCLC.

Asset Subtitle

Baohui Han

Meta Tag

Speaker Baohui Han

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

KRAS-mutant non-small cell lung cancer

therapeutic strategy

KRAS mutation

NSCLC

KRAS mutation subtypes

functional analysis

mechanism analysis

multi-omics analysis

signaling pathways

anti-tumor efficacy