2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.06: Aurora Kinase A Inhibition Potentiates KRASG12C Inhibition and Overcomes Resistance to Sotorasib in Lung Cancer

PP01.06: Aurora Kinase A Inhibition Potentiates KRASG12C Inhibition and Overcomes Resistance to Sotorasib in Lung Cancer

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The document provides a detailed analysis of the effectiveness of combining the AURKA inhibitor VIC-1911 with the KRASG12C inhibitor sotorasib in treating KRASG12C-mutated lung cancer, which often develops resistance to single-drug therapies. This study shows that the combination of VIC-1911 with sotorasib, as well as with the WEE1 inhibitor adavosertib, has synergistic antitumor effects. The AURKA inhibitor significantly enhances the efficacy of sotorasib, delaying acquired resistance.<br /><br />Key findings demonstrate that VIC-1911 prevents the rebound of phosphorylated ERK1/2 and pp90RSK1, which is typically seen after 96 hours of sotorasib treatment. In xenograft models, the combination treatments led to significant tumor regression. In particular, AURKA is identified as a critical player in both intrinsic and acquired resistance mechanisms to sotorasib, with its inhibition offering potential therapeutic benefits.<br /><br />The research encompassed in vitro experiments, including cell viability assays and Western blotting, and in vivo studies using xenograft models to test these drug combinations. The findings from these experiments suggest that AURKA plays a crucial role in centrosome maturation and mitosis, and its inhibition can disrupt adaptive resistance pathways in lung cancer therapy.<br /><br />Furthermore, the study highlights the therapeutic promise of combining AURKA and WEE1 inhibition in overcoming acquired resistance. The results emphasize that exploring AURKA and WEE1 inhibitor combinations could be crucial for enhancing treatment effectiveness in KRASG12C-mutated cancers. <br /><br />Overall, the research underscores the potential for combination therapies to extend the efficacy and utility of existing targeted treatments, providing new avenues for overcoming drug resistance in aggressive lung cancers.

Asset Subtitle

Jong Woo Lee

Keywords

AURKA inhibitor

VIC-1911

KRASG12C inhibitor

sotorasib

lung cancer

drug resistance

synergistic effects

adavosertib

xenograft models

combination therapy