Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 or PIP3) mediates signalling pathways as a second messenger inPhosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 or PIP3) mediates signalling pathways as a second messenger inresponse to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the ‘RNAworld’, physiological RNA–phospholipid interactions and their involvement in essential cellular processes have remained amystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, longintergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP3at the single-nucleotide level, facilitating AKT–PIP3 interaction and consequent enzymatic activation. LINK-A-dependent AKThyperactivation leads to tumorigenesis and resistance to AKT inhibitors. Genomic deletions of the LINK-A PIP3-binding motifdramatically sensitized breast cancer cells to AKT inhibitors. Furthermore, meta-analysis showed the correlation between LINK-Aexpression and incidence of a single nucleotide polymorphism (rs12095274: A>G), AKT phosphorylation status, and pooroutcomes for breast and lung cancer patients. PIP3-binding lncRNA modulates AKT activation with broad clinical implications.