Epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy for non-small lung cancer (NSCLC). Mitogen-inducible gene 6 (Mig6) is known to be a negative feedback regulator of EGFR. Mig6 inhibits EGFR kinase activity and promote wild-type EGFR trafficking to the degradation pathway. Down-regulation of Mig6 is found in poor prognostic NSCLC. Previous gene array analysis results suggested that Mig6 is downregulated by runt-related transcription factor 1 (RUNX1), yet the detailed relationship between RUNX1 and Mig6 in NSCLC has not been elucidated. Herein we demonstrate that RUNX1 inhibition is effective for wild-type EGFR NSCLC. Tet-inducible shRNA mediated RUNX1 knockdown in wild-type EGFR cell line LU99A led to the increased expression of Mig6 and decreased expression of phosphorylated form of EGFR as well as deactivation of EGFR/ERK pathway. RUNX1 knockdown subsequently induced apoptosis in LU99A cells. Silencing of Mig6 in LU99A cells promoted the proliferation of these cancer cells and increased expression of phosphorylated form of EGFR, highlighting the importance of this EGFR signaling cascade in the maintenance of wild-type EGFR NSCLC. Indeed, RUNX1 overexpression promoted cell proliferation and decreased expression of Mig6 and increased phosphorylated form of EGFR. Notably Mig6 knockdown in RUNX1 knockdown LU99A cells increased their proliferation rates, indicating that Mig6 plays an important role in RUNX1-mediated pro-oncogenic pathway. We next examined the efficacy of a novel small molecule which specifically binds and inhibits the RUNX1 (We named it as CM). CM was drastically effective for wild-type EGFR NSCLC cell lines A549 and LU99A which are naturally resistant to EGFR Tyrosine kinase inhibitor: gefitinib. In addition, CM suppressed tumor growth of xeno-transplanted A549 cells in immune-deficient mice in vivo. Our study underscores the importance of RUNX1 inhibition therapy in the management of gefitinib-resistant NSCLC patients.

Citation Format: Akihiko Matsuo. RUNX1 controls EGFR signaling pathway in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2017-3516