Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of -catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which -catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of -catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call adaptive persisters. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with -catenin, leading to increased stability and activation of -catenin. We demonstrate that the combination of EGFR-TKI and a -catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and -catenin inhibition in patients with EGFR mutant lung cancer.

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Arasada RR, Shilo K, Yamada T, Zhang J, Yano S, Ghanem R, Wang W, Takeuchi S, Fukuda K, Katakami N, Tomii K, Ogushi F, Nishioka Y, Talabere T, Misra S, Duan W, Fadda P, Rahman MA, Nana-Sinkam P, Evans J, Amann J, Tchekneva EE, Dikov MM, Carbone DP