2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.05: Targeting MUC16-Mediated KRASi Resistance in NSCLC

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The study investigates the mechanism involved in MUC16-mediated resistance to KRAS inhibitors (KRASi) in non-small cell lung cancer (NSCLC), focusing on a novel therapeutic strategy using a chimeric monoclonal antibody, mAb5E6. NSCLC cases with KRAS mutations, particularly KRASG12C, present challenges due to limited treatment responses to current KRAS inhibitors like sotorasib (AMG510) and adagrasib (MRTX849). The overexpression of MUC16 is linked with KRASi resistance, aggressive tumor behaviors, and poor patient outcomes in NSCLC.<br /><br />Chimeric mAb5E6 targets the unique epitope on the surface-tethered carboxy terminal domain of MUC16 (MUC16-Cter), opting to overcome the limits of existing antibodies, which predominantly target the shed form, CA125, obstructing efficient tumor cell binding. In preclinical models including cell lines, organoids, and xenograft models, mAb5E6 demonstrated significant anti-proliferative and anti-tumor activities by modulating the activity of the pFAK/p70S6K signaling axis, thereby curtailing epithelial-to-mesenchymal transition (EMT) processes associated with metastasis.<br /><br />The study further highlights that mAb5E6, when combined with AMG-510, shows a synergistic effect, reducing tumor burden more effectively compared to AMG-510 alone. This suggests the dual administration could enhance treatment efficacy for patients exhibiting KRASG12C mutations. Real-time kinetics assessments using surface plasmon resonance (SPR) affirmed the high-affinity binding of chimeric mAb5E6, ensuring specificity against MUC16 without competing with soluble CA125.<br /><br />Conclusively, this research supports chimeric mAb5E6 as a promising therapeutic agent to counteract KRASi resistance and improve NSCLC outcomes by targeting the MUC16 pathway, with future directions aimed at further dissecting its mechanism and evaluating its impact within the tumor microenvironment.

Asset Subtitle

Ashu Shah

Keywords

MUC16-mediated resistance

KRAS inhibitors

non-small cell lung cancer

chimeric monoclonal antibody

mAb5E6

KRASG12C mutations

tumor cell binding

epithelial-to-mesenchymal transition

synergistic effect

tumor microenvironment