2. Academic Validation
  3. Identification of VPS34-PI(3)P-FEN1-mediated DNA repair pathway as a potential drug target to overcome chemoresistance

Identification of VPS34-PI(3)P-FEN1-mediated DNA repair pathway as a potential drug target to overcome chemoresistance

  • Biochem Biophys Res Commun. 2023 Jun 27;674:27-35. doi: 10.1016/j.bbrc.2023.06.079.
Xiaobing Zhang 1,  Songsong Dan 2,  Xiao Pan 3,  Jingchao Li 3,  Qucheng Wei 4,  Liming Huang 5,  Bo Kang 6,  Cheng Chen 7
Affiliations

Affiliations

  • 1 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • 2 School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 3 College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 4 Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5 Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang, 312000, China.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China. Electronic address: [email protected].
  • 7 School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang, 312000, China. Electronic address: [email protected].
PMID: 37393641 DOI: 10.1016/j.bbrc.2023.06.079
Abstract

Intrinsic or acquired chemoresistance represents a major obstacle in Cancer treatment. Multiple mechanisms can contribute to Cancer cells' resistance to chemotherapy. Among them, an aberrantly strengthened DNA repair mechanism is responsible for a large proportion of drug resistance to alkylating agents and radiation therapy. In Cancer cells, damping overactivated DNA repair system can overcome survival advantages conferred by chromosomal translocations or mutations and lead to cytostatic effects or cytotoxic. Therefore, selectively targeting DNA repair system in Cancer cells holds promise for overcoming chemoresistance. In this study, we revealed that the endonuclease FLAP Endonuclease 1 (FEN1), essential for DNA replication and repair, directly interacts with phosphatidylinositol 3-phosphate [PI(3)P], and FEN1-R378 is the primary PI(3)P-binding site. PI(3)P-binding deficient FEN1 mutant (FEN1-R378A) cells exhibited abnormal chromosomal structures and were hypersensitized to DNA damage. The PI(3)P-mediated FEN1 functionality was essential for repairing DNA damages caused by multiple mechanisms. Furthermore, Vps34, the major PI(3)P synthesizing Enzyme, was negatively associated with patients' survival in various Cancer types, and Vps34 inhibitors significantly sensitized chemoresistant Cancer cells to genotoxic agents. These findings open up an avenue for counteracting chemoresistance by targeting VPS34-PI(3)P-mediated DNA repair pathway, and call for assessing the efficacy of this strategy in patients suffering from chemoresistance-mediated Cancer recurrence in clinical trials.

Keywords

Chemoresistance; DNA repair; DNA replication; FEN1; PI(3)P; VPS34.

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