ROR1 Mediates EGFR Signaling in Lung Adenocarcinoma

Some cancers are dependent on aberrant activation of lineage-specific developmental regulators that drive proliferation of particular cell types. Lung adenocarcinomas have previously been shown to be dependent on NK2 homeobox 1 (NKX2-1), a homeodomain transcription factor that plays an essential role in lung development. Yamaguchi and colleagues sought to characterize the downstream events of NKX2-1 activation by performing microarray analysis of a human peripheral lung epithelial cell line stably expressing NKX2-1 and identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as one of the most highly upregulated genes. Chromatin immunoprecipitation showed that ROR1 is a direct target of NKX2-1, and coexpression of NKX2-1 and ROR1 was observed in a panel of lung adenocarcinoma patient samples. Knockdown of ROR1 inhibited lung adenocarcinoma growth in vitro and suppressed xenograft tumor growth, indicating that induction of ROR1 by NKX2-1 is required for tumor cell survival. The authors found that ROR1 repressed proapoptotic p38 signaling, and in response to epidermal growth factor (EGF), ROR1 bound to EGF receptor (EGFR) and led to activation of the PI3K pathway by promoting the activation of ERBB3 by EGFR and by phosphorylating SRC. These findings suggest that ROR1 sustains a favorable balance of prosurvival signaling and mediates the downstream effects of EGF signaling. Therefore, ROR1 may be an attractive therapeutic target in lung adenocarcinomas, which frequently harbor activating EGFR mutations and develop secondary resistance mutations following treatment with EGFR inhibitors such as gefitinib. ROR1 knockdown not only suppressed the growth of gefitinib-resistant, EGFR-mutant lung adenocarcinoma cells but also suppressed gefitinib-sensitive, EGFR wild-type cells, suggesting that lung adenocarcinoma cells are dependent on ROR1 for survival regardless of EGFR mutational status and that targeting ROR1 may be an effective therapeutic strategy for this disease.

Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 2012;21:348–61.

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