IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33037-x.html
   My bibliography  Save this article

An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms

Author

Listed:
  • Hongjuan Yao

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Wenping Song

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
    Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital)

  • Rui Cao

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
    North China University of Science and Technology)

  • Cheng Ye

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
    Tianjin Municipal Health Commission)

  • Li Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Hebing Chen

    (Beijing Institute of Radiation Medicine)

  • Junting Wang

    (Beijing Institute of Radiation Medicine)

  • Yuchen Shi

    (Beijing University of Chinese Medicine)

  • Rui Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Yi Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Xiujun Liu

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Xiaofei Zhou

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Rongguang Shao

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

  • Liang Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC))

Abstract

Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.

Suggested Citation

  • Hongjuan Yao & Wenping Song & Rui Cao & Cheng Ye & Li Zhang & Hebing Chen & Junting Wang & Yuchen Shi & Rui Li & Yi Li & Xiujun Liu & Xiaofei Zhou & Rongguang Shao & Liang Li, 2022. "An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33037-x
    DOI: 10.1038/s41467-022-33037-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33037-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33037-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Andrew V. Biankin & Nicola Waddell & Karin S. Kassahn & Marie-Claude Gingras & Lakshmi B. Muthuswamy & Amber L. Johns & David K. Miller & Peter J. Wilson & Ann-Marie Patch & Jianmin Wu & David K. Chan, 2012. "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes," Nature, Nature, vol. 491(7424), pages 399-405, November.
    2. Claire Vennin & Pauline Mélénec & Romain Rouet & Max Nobis & Aurélie S. Cazet & Kendelle J. Murphy & David Herrmann & Daniel A. Reed & Morghan C. Lucas & Sean C. Warren & Zehra Elgundi & Mark Pinese &, 2019. "CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan," Nature Communications, Nature, vol. 10(1), pages 1-22, December.
    3. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. James T. Topham & Erica S. Tsang & Joanna M. Karasinska & Andrew Metcalfe & Hassan Ali & Steve E. Kalloger & Veronika Csizmok & Laura M. Williamson & Emma Titmuss & Karina Nielsen & Gian Luca Negri & , 2022. "Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Bárbara Andrade Barbosa & Saskia D. Asten & Ji Won Oh & Arantza Farina-Sarasqueta & Joanne Verheij & Frederike Dijk & Hanneke W. M. Laarhoven & Bauke Ylstra & Juan J. Garcia Vallejo & Mark A. Wiel & Y, 2021. "Bayesian log-normal deconvolution for enhanced in silico microdissection of bulk gene expression data," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Shigekazu Murakami & Shannon M. White & Alec T. McIntosh & Chan D. K. Nguyen & Chunling Yi, 2023. "Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Jonathan J. Swietlik & Stefanie Bärthel & Chiara Falcomatà & Diana Fink & Ankit Sinha & Jingyuan Cheng & Stefan Ebner & Peter Landgraf & Daniela C. Dieterich & Henrik Daub & Dieter Saur & Felix Meissn, 2023. "Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Gregor Werba & Daniel Weissinger & Emily A. Kawaler & Ende Zhao & Despoina Kalfakakou & Surajit Dhara & Lidong Wang & Heather B. Lim & Grace Oh & Xiaohong Jing & Nina Beri & Lauren Khanna & Tamas Gond, 2023. "Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Jérémy Guillot & Chloé Dominici & Adrien Lucchesi & Huyen Thi Trang Nguyen & Angélique Puget & Mélanie Hocine & Martha M. Rangel-Sosa & Milesa Simic & Jérémy Nigri & Fabienne Guillaumond & Martin Bigo, 2022. "Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. S. Randriamanantsoa & A. Papargyriou & H. C. Maurer & K. Peschke & M. Schuster & G. Zecchin & K. Steiger & R. Öllinger & D. Saur & C. Scheel & R. Rad & E. Hannezo & M. Reichert & A. R. Bausch, 2022. "Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Yalan Deng & Xianghou Xia & Yang Zhao & Zilong Zhao & Consuelo Martinez & Wenjuan Yin & Jun Yao & Qinglei Hang & Weiche Wu & Jie Zhang & Yang Yu & Weiya Xia & Fan Yao & Di Zhao & Yutong Sun & Haoqiang, 2021. "Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    9. Marie-Eve Wedge & Victoria A. Jennings & Mathieu J. F. Crupi & Joanna Poutou & Taylor Jamieson & Adrian Pelin & Giuseppe Pugliese & Christiano Tanese Souza & Julia Petryk & Brian J. Laight & Meaghan B, 2022. "Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Meilin Xue & Youwei Zhu & Yongsheng Jiang & Lijie Han & Minmin Shi & Rui Su & Liwen Wang & Cheng Xiong & Chaofu Wang & Ting Wang & Shijie Deng & Dong Wu & Yizhi Cao & Lei Dong & Fan Bai & Shulin Zhao , 2023. "Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    11. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    12. Haochen Zhang & Elias-Ramzey Karnoub & Shigeaki Umeda & Ronan Chaligné & Ignas Masilionis & Caitlin A. McIntyre & Palash Sashittal & Akimasa Hayashi & Amanda Zucker & Katelyn Mullen & Jungeui Hong & A, 2023. "Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    13. Yanfen Zheng & Xingyang Li & Shuang Deng & Hongzhe Zhao & Ying Ye & Shaoping Zhang & Xudong Huang & Ruihong Bai & Lisha Zhuang & Quanbo Zhou & Mei Li & Jiachun Su & Rui Li & Xiaoqiong Bao & Lingxing Z, 2023. "CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    14. Peter Bailey & Rachel A. Ridgway & Patrizia Cammareri & Mairi Treanor-Taylor & Ulla-Maja Bailey & Christina Schoenherr & Max Bone & Daniel Schreyer & Karin Purdie & Jason Thomson & William Rickaby & R, 2023. "Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    15. Michael Papanicolaou & Amelia L. Parker & Michelle Yam & Elysse C. Filipe & Sunny Z. Wu & Jessica L. Chitty & Kaitlin Wyllie & Emmi Tran & Ellie Mok & Audrey Nadalini & Joanna N. Skhinas & Morghan C. , 2022. "Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    16. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    17. Charlie Saillard & Flore Delecourt & Benoit Schmauch & Olivier Moindrot & Magali Svrcek & Armelle Bardier-Dupas & Jean Francois Emile & Mira Ayadi & Vinciane Rebours & Louis de Mestier & Pascal Hammel, 2023. "Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    18. Zhaoqi Shu & Minghe Fan & Bo Tu & Zhiheng Tang & Haojie Wang & Haimeng Li & Hengchao Li & Meng Yuan & Jingru Bai & Sihan Huo & Lina Wang & Wei-Guo Zhu & Wei Wang & Xiaoyun Liu & Shaokun Shu & Ying Zha, 2023. "The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Michelle Maurin & Mohammadreza Ranjouri & Cristina Megino-Luque & Justin Y. Newberg & Dongliang Du & Katelyn Martin & Robert E. Miner & Mollie S. Prater & Dave Keng Boon Wee & Barbara Centeno & Shondr, 2023. "RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Siqi Li & Kun Li & Kang Wang & Haoyuan Yu & Xiangyang Wang & Mengchen Shi & Zhixing Liang & Zhou Yang & Yongwei Hu & Yang Li & Wei Liu & Hua Li & Shuqun Cheng & Linsen Ye & Yang Yang, 2023. "Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33037-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.