The LINK-A lncRNA interacts with PtdIns(3,4,5)P 3 to hyperactivate AKT and confer resistance to AKT inhibitors.

Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P ₃ or PIP ₃ ) mediates signalling pathways as a second messenger in response to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the 'RNA world', physiological RNA-phospholipid interactions and their involvement in essential cellular processes have remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, long intergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP ₃ at the single-nucleotide level, facilitating AKT-PIP ₃ interaction and consequent enzymatic activation. LINK-A-dependent AKT hyperactivation leads to tumorigenesis and resistance to AKT inhibitors. Genomic deletions of the LINK-A PIP ₃ -binding motif dramatically sensitized breast cancer cells to AKT inhibitors. Furthermore, meta-analysis showed the correlation between LINK-A expression and incidence of a single nucleotide polymorphism (rs12095274: A > G), AKT phosphorylation status, and poor outcomes for breast and lung cancer patients. PIP ₃ -binding lncRNA modulates AKT activation with broad clinical implications.