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. 2020 Nov 15;26(22):5962-5973.
doi: 10.1158/1078-0432.CCR-20-2077. Epub 2020 Sep 8.

Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer

Yuta Adachi  1 , Kentaro Ito  1 , Yuko Hayashi  1 , Ryo Kimura  1 , Tuan Zea Tan  2 , Rui Yamaguchi  3   4 , Hiromichi Ebi  5   6
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Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer

Yuta Adachi et al. Clin Cancer Res. .

Abstract

Purpose: KRAS is among the most commonly mutated oncogene in cancer including non-small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify.

Experimental design: To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C-mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed.

Results: KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR-IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510.

Conclusions: Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.

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References

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