WFDC3 sensitizes colorectal cancer to chemotherapy by regulating ATM / ATR kinase signaling pathway

Chemoresistance is an ongoing challenge for colorectal cancer (CRC) that significantly compromises the anti-tumor efficacy of current drugs. Identifying effective targets or drugs for overcoming chemoresistance is urgently needed. Our previous study showed that WFDC3 served as a tumor suppressor that hindered CRC metastasis. However, the function of WFDC3 in chemotherapy remains unknown. Here, we found that high WFDC3 expression in CRC patients treated with oxaliplatin was associated with a better prognosis. Concordantly, overexpression of WFDC3 significantly increased sensitivity to oxaliplatin in CRC cells, whereas knocking down WFDC3 led to oxaliplatin resistance. In addition, WFDC3 promoted oxaliplatin-mediated suppression of tumor growth in vivo. Subsequently, we found that WFDC3 could enhance oxaliplatin-induced DNA damage through inhibiting ATM/ATR signaling. WFDC3 knockdown showed the opposite effects. Moreover, a combination treatment of oxaliplatin and inhibitors for ATM or ATR partially reversed chemoresistance to oxaliplatin in CRC cells with low WFDC3 expression. Our results demonstrate that WFDC3 is possibly a biomarker for increasing oxaliplatin sensitivity in CRC by modulating ATM/ATR kinase signaling. Thus, a combination of oxaliplatin with an ATM or ATR inhibitor is a potential treatment option for improving CRC outcome.