Yiheng Huang, Elizabeth McCulla, Jihan Park, Annabel Yang, Timothy Jho, Angelica Lin, Jie Xu, Kari Wilder-Romans, Luke D Hess, Jing Li, Ningning Liang, Ziqing Zhu, Deven Kothari, Karen Jin, Sarah Kim, Sanduni H Premathilaka, Bo Wen, Duxin Sun, Michelle Vinco, Sean P Ferris, Meredith A Morgan, Theodore S Lawrence, Yatrik M Shah, Menggang Yu, Molly E Heft Neal, J Chad Brenner, Suranganie Dharmawardhane, Jose F Rodriguez-Orengo, Daniel R Wahl, Weihua Zhou
Radiation resistance remains a major barrier to cancer treatment. We identify Abi-1-S323 phosphorylation as a biomarker of distinct DNA repair states and therapeutic vulnerabilities, providing a framework for precision radiosensitization.
UNLABELLED: Radiation therapy (RT) resistance remains a major clinical challenge, yet biomarkers guiding precision radiosensitization are lacking. We previously demonstrated that Rac1 promotes RT resistance in glioblastoma (GBM) by inducing Abi-1-S323 dephosphorylation and enhancing non-homologous end joining (NHEJ). Here, we identify Abi-1-S323 as a key regulator of DNA repair states and a determinant of therapeutic efficacy in human cancers. Clinically, loss of Abi-1-S323 phosphorylation was associated with poor outcomes in patients with RT-treated GBM. Bioinformatic analyses revealed that non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) are among the cancers with frequent RAC1 amplification, suggesting that these tumor types may have increased Rac1-Abi-1 signaling activity. Loss of Abi-1-S323 phosphorylation also predicted poor outcomes in patients with RT-treated HNC. Consistent with these clinical observations, high Rac1 activity and low Abi-1-S323 phosphorylation were associated with enhanced DNA double-strand break repair and radioresistance in NSCLC and HNC models, whereas genetic or pharmacological inhibition of this signaling impaired DNA repair and radiosensitized tumors in vitro and in vivo . Mechanistically, we identified CHK1 as a kinase that phosphorylates Abi-1 at S323 and defines an alternative homologous recombination (HR)-dependent repair state. Tumors with high Rac1-Abi-1 signaling exhibited elevated NHEJ capacity and were selectively radiosensitized by Rac1 inhibition, whereas tumors with low Rac1-Abi-1 signaling displayed high CHK1 activity, preferentially relied on HR, and were selectively radiosensitized by CHK1 inhibition. These findings establish Abi-1-S323 as a biomarker defining therapeutically distinct DNA repair states and provide a framework for precision radiosensitization.
SIGNIFICANCE: Radiation resistance remains a major barrier to cancer treatment. We identify Abi-1-S323 phosphorylation as a biomarker of distinct DNA repair states and therapeutic vulnerabilities, providing a framework for precision radiosensitization.