The c‐Src/LIST Positive Feedback Loop Sustains Tumor Progression and Chemoresistance

Chemotherapy resistance and treatment failure hinder clinical cancer treatment. Src, the first mammalian proto‐oncogene to be discovered, is a valuable anti‐cancer therapeutic target. Although several c‐Src inhibitors have reached the clinical stage, drug resistance remains a challenge during treatment. Herein, a positive feedback loop between a previously uncharacterized long non‐coding RNA (lncRNA), which the authors renamed lncRNA‐inducing c‐Src tumor‐promoting function (LIST), and c‐Src is uncovered. LIST directly binds to and regulates the Y530 phosphorylation activity of c‐Src. As a c‐Src agonist, LIST promotes tumor chemoresistance and progression in vitro and in vivo in multiple cancer types. c‐Src can positively regulate LIST transcription by activating the NF‐κB signaling pathway and then recruiting the P65 transcription factor to the LIST promoter. Interestingly, the LIST/c‐Src interaction is associated with evolutionary new variations of c‐Src. It is proposed that the human‐specific LIST/c‐Src axis renders an extra layer of control over c‐Src activity. Additionally, the LIST/c‐Src axis is of high physiological relevance in cancer and may be a valuable prognostic biomarker and potential therapeutic target.