2. Academic Validation
  3. Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype

Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype

  • Cell Death Dis. 2021 Oct 21;12(11):978. doi: 10.1038/s41419-021-04270-x.
Jiayin Deng  # 1 2 3 4,  Ai-Ling Tian  # 2 3 4,  Hui Pan 2 3 4,  Allan Sauvat 3 4,  Marion Leduc 3 4,  Peng Liu 3 4,  Liwei Zhao 3 4,  Shuai Zhang 3 4,  Hui Chen 2 3 4,  Valérie Taly 4,  Pierre Laurent-Puig 4 5,  Laura Senovilla 3 4 5,  Yingqiu Li 6,  Guido Kroemer 7 8 9 10 11,  Oliver Kepp 12 13
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 2 Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France.
  • 3 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
  • 4 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France.
  • 5 Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain.
  • 6 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. lsslyq@mail.sysu.edu.cn.
  • 7 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France. kroemer@orange.fr.
  • 8 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. kroemer@orange.fr.
  • 9 Pôle de Biologie, Institut du Cancer Paris Carpem, APHP, Hôpital Européen Georges Pompidou, Paris, France. kroemer@orange.fr.
  • 10 Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, China. kroemer@orange.fr.
  • 11 Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. kroemer@orange.fr.
  • 12 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France. captain.olsen@gmail.com.
  • 13 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. captain.olsen@gmail.com.
  • # Contributed equally.
PMID: 34675191 DOI: 10.1038/s41419-021-04270-x
Abstract

Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of Apoptosis and Autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.

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