CDC7 stabilized by KRAS signaling reactivation impairs chemosensitivity in KRAS-mutant colorectal cancer
- Pharmacol Res. 2025 Dec:222:108027. doi: 10.1016/j.phrs.2025.108027.
- 1. Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
- 2. Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- 3. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
- 4. The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 5. Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; School of Medicine, Hangzhou City University, Hangzhou, China.
- 6. Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 7. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China. Electronic address: [email protected].
- 8. Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
KRAS, the most frequently mutated oncogene in colorectal Cancer (CRC), presents a formidable therapeutic challenge. While 5-fluorouracil (5-FU) and oxaliplatin remain the cornerstone of chemotherapy for KRAS-mutant CRC, their efficacy is frequently undermined by intrinsic and acquired resistance. Unravelling the shared mechanisms underlying sensitivity to both 5-FU and oxaliplatin could unveil novel strategies to restore chemosensitivity. We identified cell division cycle 7 (CDC7), a highly conserved serine/threonine kinase essential for DNA replication, as a crucial regulator of chemotherapy response in KRAS-mutant CRC. Mechanistically, genotoxic stress triggered adaptive reactivation of KRAS-MAPK/PI3K pathways, which cooperatively stabilized CDC7 by disrupting HRD1-mediated cytoplasmic degradation and promoting its nuclear translocation. Increased nuclear CDC7 pools licensed DNA damage tolerance. The stress-adaptive process was a shared mechanism for both 5-FU and oxaliplatin. Genetic ablation or pharmacological inhibition of CDC7 attenuated CRC proliferation and demonstrated a synergistic effect with chemotherapy in vitro and in vivo. Importantly, this work elucidated the subcellular distribution and proteostasis regulation of CDC7 under genotoxic stress, which is a switch for chemosensitivity in KRAS mutant CRC. These findings established CDC7 as a therapeutic vulnerability in KRAS-mutant CRC and provided a rationale for targeting CDC7 as a therapeutic strategy to restore chemosensitivity to 5-FU/oxaliplatin.