2. Academic Validation
  3. CDC7 stabilized by KRAS signaling reactivation impairs chemosensitivity in KRAS-mutant colorectal cancer

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.
Ruilin Wu 1,  Yue Liu 2,  Junwei Fu 2,  Tianhua Zhou 3,  Ronggui Hu 4,  Bo Yang 5,  Qiaojun He 6,  Tao Yuan 7,  Hong Zhu 8
Affiliations

Affiliations

  • 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].
PMID: 41207349 DOI: 10.1016/j.phrs.2025.108027
Abstract

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.

Keywords

CDC7; Chemosensitivity; KRAS signaling reactivation; KRAS-mutant CRC; Proteostasis regulation.

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