Given that we identified p65BTK in synthetic lethal loss-of-function screen aimed at identifying actionable targets in drug-resistant cells, the role of the novel isoform was experimentally explored in in vitro (cell lines), ex vivo (patient-derived organoids) and in vivo (tumor xenografts) models of 5FU-resistant CRCs using both, functional genetic approaches (shRNA/siRNA) and chemical approaches (BTK inhibitors). The gene discussed is BTK; the disease is neoplasm.