2. Academic Validation
  3. Tumor-derived apolipoprotein E confers resistance to temozolomide in pancreatic neuroendocrine tumors

Tumor-derived apolipoprotein E confers resistance to temozolomide in pancreatic neuroendocrine tumors

  • Cell Death Dis. 2025 Dec 13. doi: 10.1038/s41419-025-08317-1.
Xin Lou # 1 2 3 4 5,  Yihua Shi # 1 2 3 4 5,  Yi Qin # 1 2 3 4 5,  Wuhu Zhang # 1 2 3 4 5,  Zeng Ye 1 2 3 4 5,  Fei Wang 1 2 3 4 5,  Yan Wang 1 2 3 4 5,  Tian Ding 1 2 3 4 5,  Desheng Jing 1 2 3 4 5,  Guixiong Fan 1 2 3 4 5,  Yue Zhang 6,  Xuemin Chen 6,  Xiaowu Xu 7 8 9 10 11,  Xianjun Yu 12 13 14 15 16,  Shunrong Ji 17 18 19 20 21,  Junfeng Xu 22 23 24 25 26
Affiliations

Affiliations

  • 1 Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 4 Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
  • 5 Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 6 The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China.
  • 7 Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 8 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 9 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 10 Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 11 Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • 12 Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 13 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 14 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 15 Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 16 Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • 17 Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 18 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 19 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 20 Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 21 Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • 22 Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 23 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 24 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 25 Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 26 Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 41390817 DOI: 10.1038/s41419-025-08317-1
Abstract

Temozolomide (TMZ) is a first-class clinical drug for patients with pancreatic neuroendocrine tumors (pNETs). However, the therapeutic effects of TMZ are limited because of the chemoresistance of pNET cells, which has not been fully elucidated. Here, we demonstrate that the reprogramming of lipid metabolism regulates TMZ resistance in patients with pNETs. Via integrated multiomics Sequencing, Apolipoprotein E (apoE), which is a critical lipid carrier, was identified to be highly increased in the tissue and blood plasma of patients in the TMZ treatment group compared with those in the control group. Further mechanistic studies revealed that TMZ treatment promotes the expression and secretion of apoE, which binds to its surface receptor known as scavenger receptor class B member 1 (SCARB1), thus leading to increased uptake of exogenous lipids to remodel cellular lipid metabolism and activation of the homologous recombination repair (HRR) pathway to repair DNA damage via the β-catenin-BRCA1/2 axis. The interruption of APOE-mediated lipid uptake via a SCARB1 inhibitor named as block lipid transport-1 (BLT-1), suppressed TMZ-induced HRR activation and sensitized tumor cells to TMZ treatment in preclinical models, including PDCs, PDOs, and PDXs. In addition, apoE expression levels were shown to be positively correlated with BRCA1/2 expression in clinical specimens and online databases. This study reveals a new functional role of apoE that leads to chemoresistance in patient treatment. Our findings suggest the potential of combined administration of BLT-1 to overcome TMZ chemoresistance and improve treatments for patients with pNETs.

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