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EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-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 we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-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 β-catenin inhibition in patients with EGFR mutant lung cancer., Treatment of EGFR mutant non-small cell lung cancer (NSCLC) often develops resistance to EGFR TKIs. In this study, the authors discover a non-canonical activation of β-catenin signaling through Notch3 as a mechanism of adaptation to and resistance to EGFR TKI treatment in NSCLC.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) usually cause dramatic responses in EGFR-mutant lung cancer, but different patients with identical drivers have widely different progression-free intervals, and resistance universally develops. In those cases without pre-existing resistant clones, even though every cell expresses the driver, some tumor clonogens survive in order to acquire target reactivation or bypass resistance mechanisms. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Our transcriptome analysis identified that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We have previously reported that EGFR-TKI treatment rapidly activates Notch3, and here our co-immunoprecipitation studies identified a physical association of Notch3 with β-catenin, which in turn leads to increased stability and activation of β-catenin. In vitro pulmosphere formation assays and in vivo limiting dilution assays reveled that adaptive persisters display characteristics of stem-like cells. Furthermore, tumor xenograft studies using HCC827 and HCC4006 demonstrate that the combination of EGFR-TKI and the β-catenin inhibitor, ICG-001 inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival. Overall, Notch3 plays a pivotal role in the maintenance of lung cancer stem cells (CSCs) and the induction of EGFR TKI mediated drug persisters with cancer stem cell like characteristics, but is difficult to selectively target. Our study finds that this effect is driven by the Notch3-dependent activation of β-catenin signaling in a non-canonical fashion. A combination of EGFR TKI and β-catenin inhibitors decreases tumor take, delays tumor recurrence and increases overall survival in EGFR mutant models. Thus, our findings provide novel insights on role of drug persistence early after EGFR TKI therapy and presents a rationale for clinical testing of EGFR TKIs with β-catenin inhibitors for the treatment of EGFR mutant NSCLC. Citation Format: Rajeswara Rao Arasada, Konstantin Shilo, Jianying Zhang, Rashelle Ghanem, Tadaaki Yamada, Seiji Yano, David Carbone. Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2839.