Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

• 成果类型: Article
• 署名作者: Yu, Zhaoliang; Deng, Peng; Chen, Yufeng; Lin, Dezheng; Liu, Shini; Hong, Jinghan; Guan, Peiyong; Chen, Jianfeng; Zhong, Min-er; Chen, Jinghong; Chen, Xiaochuan; Sun, Yichen; Wang, Yali; Wang, Peili; Cai, Zerong; Chan, Jason Yongsheng; Huang, Yulin; Xiao, Rong; Guo, Yaoyu; Zeng, Xian; Wang, Wenyu; Zou, Yifeng; Yu, Qiang; Lan, Ping; Teh, Bin Tean; Wu, Xiaojian; Tan, Jing
• 署名单位: Sun Yat Sen University; Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen University; Agency for Science Technology & Research (A*STAR); A*STAR - Genome Institute of Singapore (GIS); Sun Yat Sen University; National Cancer Centre Singapore (NCCS); Sun Yat Sen University; Sun Yat Sen University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12145
• DOI: 10.1073/pnas.2304619121
• 发表日期: 2024-02-06
• 关键词: kinase 4/6 inhibitor; histone deacetylase; cdk4/6 inhibitors; stem-cells; open-label; breast; therapy; bevacizumab; palbociclib; combination

摘要

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/ TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.