2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.03E.02 Elucidation of Trastuzumab-Deruxtecan Resistance Mechanisms using in Vivo Xenograft Model Reflecting Pharmacokinetics

EP.03E.02 Elucidation of Trastuzumab-Deruxtecan Resistance Mechanisms using in Vivo Xenograft Model Reflecting Pharmacokinetics

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The document primarily discusses a study conducted to understand the mechanisms of resistance to Trastuzumab-deruxtecan (T-DXd), an antibody-drug conjugate used to treat HER2-positive cancers, including breast and gastric cancers, and non-small cell lung cancer (NSCLC). The study involved the use of a xenograft model to mimic human pharmacokinetics and induce resistance in cancer cells. <br /><br />The researchers specifically established a T-DXd resistant line of gastric cancer cells, termed N87AR, by repeated in vivo treatment. These N87AR cells showed maintained HER2 protein expression but demonstrated resistance to T-DXd and cross-resistance to other Topoisomerase I inhibitors. A key finding of the study was that N87AR cells exhibited elevated levels of the ABCG2 protein compared to their non-resistant counterparts. This overexpression correlated with their resistance to T-DXd both in vitro and in vivo.<br /><br />The study further revealed that the resistance could be mitigated by knockdown of ABCG2 using siRNA or by the use of ABCG2 inhibitors, such as KO143. This led to a re-sensitization of the cancer cells to T-DXd, both in vitro and when the ABCG2 inhibitors were used in live animal models.<br /><br />The findings suggest a significant role of ABCG2 in mediating T-DXd resistance, indicating the potential for ABCG2 inhibitors to overcome this resistance. The authors stress the importance of developing methods to detect ABCG2 expression clinically and the potential clinical implications for ABCG2 inhibitors in treating resistant HER2-positive cancers. <br /><br />Overall, the study showcases the importance of understanding drug resistance mechanisms and highlights a possible intervention strategy to enhance the efficacy of T-DXd by targeting ABCG2 overexpression in resistant cancer cells.

Asset Subtitle

Seiji Yano

Meta Tag

Speaker Seiji Yano

Topic Tumor Biology – Translational Biology

Keywords

Trastuzumab-deruxtecan

HER2-positive cancers

xenograft model

ABCG2 protein

drug resistance

N87AR cells

Topoisomerase I inhibitors

siRNA knockdown

ABCG2 inhibitors

cancer treatment