2024 World Conference on Lung Cancer (WCLC) - Posters-P3.12E.03 Anti-Tumor Efficacy of HRS-4642 and its Potential Combination with Proteasome Inhibition in KRAS G12D-Mutant Cancer

P3.12E.03 Anti-Tumor Efficacy of HRS-4642 and its Potential Combination with Proteasome Inhibition in KRAS G12D-Mutant Cancer

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The study presented focuses on the anti-tumor efficacy of the compound HRS-4642, particularly in its application to KRAS G12D-mutant cancers, which are prevalent in solid tumors and notoriously challenging to treat. Existing KRAS inhibitors are often hampered by low efficacy and short durations of effectiveness. The researchers, led by Libo Luo and colleagues primarily from the Tongji University School of Medicine and Shanghai Pulmonary Hospital, investigated the potential of HRS-4642 to selectively inhibit KRAS G12D and its performance in treating NSCLC (non-small cell lung cancer) with this mutation.<br /><br />HRS-4642 demonstrated significant anti-tumor activity when used alone in NSCLC models harboring the KRAS G12D mutation. In an innovative approach, genome CRISPR screenings revealed the proteasome as a promising synergistic target when combined with HRS-4642 treatment. Building on this finding, the proteasome inhibitor carfilzomib was paired with HRS-4642, resulting in enhanced anti-tumor efficacy compared to HRS-4642 alone.<br /><br />Additionally, the combination therapy promoted noticeable immune infiltration and activation, suggesting a potential engagement of the immune system in combating the tumors. This finding indicates that the combination of HRS-4642 with proteasome inhibition could offer a dual mechanism of action, potentially leading to more durable therapeutic responses.<br /><br />The study, supported by various Chinese grants and Jiangsu Hengrui Medicine Co., Ltd., highlights a promising therapeutic avenue for KRAS G12D-mutant cancers and underscores the importance of exploring combination therapies to overcome the limitations of current KRAS inhibitors. Further research and clinical trials will be necessary to validate these findings and potentially translate them into clinical practice.

Asset Subtitle

Shengxiang Ren

Meta Tag

Speaker Shengxiang Ren

Topic Metastatic NSCLC – Targeted Therapy

Keywords

HRS-4642

KRAS G12D-mutant

anti-tumor efficacy

non-small cell lung cancer

NSCLC

CRISPR screenings

proteasome inhibitor

carfilzomib

immune activation

combination therapy