NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma

SummaryWe and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an “Achilles' heel” in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (189 K)Download as PowerPoint slideHighlights► ROR1 is a key transcriptional target of the lineage-survival oncogene NKX2-1 ► ROR sustains a favorable balance between prosurvival and pro-apoptotic signaling ► ROR1 plays a “sustainer role” in EGFR-mediated prosurvival signaling ► ROR1 inhibition may be a therapeutic option irrespective of EGFR status