CDC7 stabilized by KRAS signaling reactivation impairs chemosensitivity in KRAS-mutant colorectal cancer

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.