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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

PLD1-driven oncogenic secretion creates a therapeutic vulnerability in chromosome 3q–amplified NSCLC

  • Xiaochao Tan1,2
  • Shike Wang2
  • Sieun Lee2
  • Guan-Yu Xiao3
  • Derrick L. Cardin1
  • Dakai Zhang3
  • Yuting Xu1
  • Chao Wu4
  • Biyao Zhou4
  • William K. Russell5
  • Guangwei Du2
5 affiliations
  1. 1Section of Hematology and Medical Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112
  2. 2Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030
  3. 3Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, KY 40536
  4. 4Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
  5. 5Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555
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Abstract

Chromosome 3q (3q) amplification is a frequent event in non–small cell lung cancer (NSCLC) and other cancer types, yet therapeutic strategies targeting oncogenic drivers within this amplicon have been unsuccessful. Our study revealed that the 3q amplicon encodes multiple Golgi-related proteins, including Phospholipase D1 (PLD1), which catalyzes the production of a potential oncogenic lipid, phosphatidic acid. We found that PLD1 is highly expressed in 3q-amplified NSCLC (3q-NSCLC) and its enzymatic activity is further boosted by coamplified PLD1 activator, ARF-like GTPase 14. High PLD1 activity is essential for 3q-NSCLC growth and metastasis. Mechanistically, PLD1 drives secretion of oncogenic factors via the carriers from the trans Golgi network to the cell surface pathway to support tumor growth. Transferrin receptor 1 (TFRC), which encodes a membrane protein, is coamplified with PLD1 and overexpressed in 3q-NSCLC. A TFRC antibody–drug conjugate (ADC) carrying a PLD1 inhibitor exhibited potential antitumor activity in mouse models. These findings establish PLD1 as a promoter of 3q-NSCLC and provide proof of concept for the development of PLD1-targeted therapies, including ADC-based approaches, for this challenging cancer subtype.

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Cite

BibTeXRIS
BibTeX
@article{tan2026pld1driven,
  title = {{PLD1-driven oncogenic secretion creates a therapeutic vulnerability in chromosome 3q–amplified NSCLC}},
  author = {Xiaochao Tan and Shike Wang and Sieun Lee and Guan-Yu Xiao and Derrick L. Cardin and Dakai Zhang and Yuting Xu and Chao Wu and Biyao Zhou and William K. Russell and Guangwei Du},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2532484123},
  url = {https://doi.org/10.1073/pnas.2532484123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - PLD1-driven oncogenic secretion creates a therapeutic vulnerability in chromosome 3q–amplified NSCLC
AU  - Xiaochao Tan
AU  - Shike Wang
AU  - Sieun Lee
AU  - Guan-Yu Xiao
AU  - Derrick L. Cardin
AU  - Dakai Zhang
AU  - Yuting Xu
AU  - Chao Wu
AU  - Biyao Zhou
AU  - William K. Russell
AU  - Guangwei Du
PY  - 2026
DA  - 2026/10/20
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2532484123
UR  - https://doi.org/10.1073/pnas.2532484123
AB  - Chromosome 3q (3q) amplification is a frequent event in non–small cell lung cancer (NSCLC) and other cancer types, yet therapeutic strategies targeting oncogenic drivers within this amplicon have been unsuccessful. Our study revealed that the 3q amplicon encodes multiple Golgi-related proteins, including Phospholipase D1 (PLD1), which catalyzes the production of a potential oncogenic lipid, phosphatidic acid. We found that PLD1 is highly expressed in 3q-amplified NSCLC (3q-NSCLC) and its enzymatic activity is further boosted by coamplified PLD1 activator, ARF-like GTPase 14. High PLD1 activity is essential for 3q-NSCLC growth and metastasis. Mechanistically, PLD1 drives secretion of oncogenic factors via the carriers from the trans Golgi network to the cell surface pathway to support tumor growth. Transferrin receptor 1 (TFRC), which encodes a membrane protein, is coamplified with PLD1 and overexpressed in 3q-NSCLC. A TFRC antibody–drug conjugate (ADC) carrying a PLD1 inhibitor exhibited potential antitumor activity in mouse models. These findings establish PLD1 as a promoter of 3q-NSCLC and provide proof of concept for the development of PLD1-targeted therapies, including ADC-based approaches, for this challenging cancer subtype.
SN  - 0027-8424
SN  - 1091-6490
ER  -