Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC. Overall design: 1. Chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K27ac or Input was performed in DLD-1 cells. 2.RNA-seq for DLD-1 cells after oxaliplatin, palbociclib or combinational treatment. 3. RNA-seq for 20 locally advanced rectal cancer (LARC) patients with neoadjuvant chemotherapy.