Using BTK or ABLPHICS, we phosphorylated tyrosine residues in a diverse sequence context,including those surrounded by neutral, acidic, or basic residues.Finally, we generated ABL-BTK PHICS using a covalent inhibitor ofBTK (i.e., ibrutinib) to induce its ABL-mediated phosphorylation;these PHICS effectively kill ibrutinib-resistant cancer cell linesand inhibit the downstream survival signaling of BTK, highlightingthe therapeutic potential of this class of molecules. This evidence concerns the gene BTK and cancer.