Salt‐inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair

Abstract

Resistance to radiotherapy remains a critical barrier in treating colorectal cancer (CRC), particularly in cases of locally advanced rectal cancer (LARC). To identify key kinases involved in CRC radioresistance, we employed a kinase-targeted CRISPR-Cas9 library screen. This approach aimed to identify potential kinase inhibitors as radiosensitizers. Our screening identified salt-inducible kinase 2 (SIK2) as a critical factor in CRC radioresistance. Increased SIK2 expression correlated with reduced tumor regression and poorer outcomes in LARC patients undergoing neoadjuvant chemoradiotherapy. The depletion of SIK2 significantly enhanced radiation-induced apoptosis and tumor regression. Mechanistically, SIK2 interacts with valosin-containing protein (VCP), promoting its hyperphosphorylation. This modification improves VCP's capacity to extract K48-linked ubiquitin-conjugated proteins from chromatin, thus aiding the recruitment of RPA and RAD51 to DNA damage sites. This mechanism strengthens homologous recombination–mediated DNA repair, which contributes to radioresistance. Importantly, ARN-3236, a SIK2 inhibitor, markedly sensitized CRC cells to radiation both in vivo and in vitro, providing a potential strategy to overcome radioresistance. In summary, our findings reveal a novel mechanism by which SIK2 contributes to the radioresistance of CRC, proposing SIK2 as a potential therapeutic target with its inhibitor significantly enhancing CRC radiotherapy efficacy.