Lavitrano M, Ianzano L, Bonomo S, et al. - Via a study of three distinct cohorts of patients, researchers revealed that p65 Bruton’s tyrosine kinase (BTK, 77 kDa non-receptor tyrosine kinase playing a crucial role in B-cell physiology where it transduces activation, proliferation, maturation, differentiation and survival signals) expression relates to histotype and cancer progression. Drug-resistant TP53-null colon cancer cells was as a model. It was illustrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of colorectal cancer (CRC, the fourth principal cause of death from cancer globally) cell lines and patient-derived organoids and significantly decreased the growth of xenografted tumors. Mechanistically, blocking p65BTK in drug-resistant cells removed a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Collectively, it was exhibited that targeting p65BTK revives the apoptotic response to chemotherapy of drug-resistant CRCs and provides a proof-of-concept for recommending the use of BTK inhibitors in combination with 5-FU as a novel therapeutic strategy in CRC patients.