2. Academic Validation
  3. Phospholipase D2 regulation by transcription factor FOXA1 promotes the drug resistance of vemurafenib in melanoma cells

Phospholipase D2 regulation by transcription factor FOXA1 promotes the drug resistance of vemurafenib in melanoma cells

  • Biochem Pharmacol. 2025 Dec;242(Pt 4):117434. doi: 10.1016/j.bcp.2025.117434.
Jun Liu 1,  Lingjun Li 2,  Cheng Wang 3,  Chenjie Liu 2,  Jinkang He 2,  Pengcheng Ma 2,  Hongyang Li 4
Affiliations

Affiliations

  • 1 Jiangsu Provincial Key Laboratory of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-target Natural Drugs, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Provincial Key Laboratory of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China.
  • 3 Department of Dermatology, Zhongda Hospital Southeast University, Nanjing 210009, China.
  • 4 Jiangsu Provincial Key Laboratory of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China. Electronic address: lihy@pumcderm.cams.cn.
PMID: 41110487 DOI: 10.1016/j.bcp.2025.117434
Abstract

The clinical effectiveness of vemurafenib that targets BRAF V600E mutation in patients with melanoma had been recognized. However, the drug resistance severely hampers the clinical application of vemurafenib. We combined metabolomics and transcriptomics analysis and found that Phospholipase D2 (PLD2), a key enzyme in choline metabolism, was significantly highly expressed in vemurafenib-resistant melanoma cells, and knockdown of PLD2 significantly increased the drug sensitivity of vemurafenib in melanoma resistant cells. Furtherly, we found that the transcription factor forkhead box protein A1 (FOXA1) positively regulated the expression of PLD2 and promoted the resistance of vemurafenib. Importantly, the knockdown of PLD2 significantly enhanced the DNA breaks induced by vemurafenib treatment, which prompted that PLD2-mediated protection from vemurafenib was responsible for the drug resistance of vemurafenib. In addition, we furtherly found that the combination of PLD2 inhibitor CAY10594 or PLD1/PLD2 dual inhibitors FIPI and vemurafenib exerted synergistic antiproliferative effects in melanoma sensitive cells. The implementation of our study systematically clarified the molecular mechanism by which the FOXA1/PLD2 functional axis mediated vemurafenib resistance via protection from DNA breaks likely subsequent to Apoptosis induction in melanoma, and proposed that targeted inhibition of PLD2 synergistically enhances the efficacy of vemurafenib or reverses its resistance, which provided us new insight for the clinical precision medicine of vemurafenib in melanoma.

Keywords

DNA breaks; Drug resistance; FOXA1; Melanoma; PLD2.

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