2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.13 High EGFR Expression Confers Acquired Resistance to Adagrasib - In Vitro Study Using KRASg12C Mutated Lung Cancer Cells

P3.03I.13 High EGFR Expression Confers Acquired Resistance to Adagrasib - In Vitro Study Using KRASg12C Mutated Lung Cancer Cells

Back to course

Pdf Summary

This study investigates the mechanisms behind acquired resistance to adagrasib, a KRASG12C inhibitor, in lung cancer cells and explores potential strategies to overcome this resistance. Adagrasib initially shows substantial tumor regression in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC), but resistance development is common and not completely understood. In this research, researchers developed adagrasib-resistant H2122 lung cancer cells by exposing them to the drug over time.<br /><br />Key findings from the study reveal that high expression of EGFR (epidermal growth factor receptor) is linked to acquired resistance to adagrasib. While there is no amplification of the EGFR gene, an increase in EGFR mRNA expression and high phosphorylation of EGFR were noted in resistant (H2122AR) cells compared to sensitive cells. These observations were confirmed through direct sequencing, phospho-RTK arrays, quantitative PCR, RNA sequencing, and immunoblot analysis.<br /><br />Further analysis demonstrated that H2122AR cells, in addition to being resistant to adagrasib, also exhibited resistance to another KRASG12C inhibitor, sotorasib. Researchers tested co-treatments combining adagrasib with afatinib, a second-generation EGFR inhibitor, which suggested that this dual blockade might be effective against resistant cells characterized by high EGFR expression.<br /><br />In summary, the study concludes that high EGFR expression, independent of gene amplification, contributes to acquired resistance to adagrasib in KRASG12C-mutated lung cancer cells. For such resistant cells with elevated EGFR protein expression, a treatment strategy employing dual inhibition of EGFR and KRASG12C may offer a promising therapeutic approach.

Asset Subtitle

Akira Hamada

Meta Tag

Speaker Akira Hamada

Topic Tumor Biology – Translational Biology

Keywords

adagrasib

KRASG12C

lung cancer

acquired resistance

EGFR expression

non-small cell lung cancer

H2122AR cells

sotorasib

afatinib

dual inhibition