2. Academic Validation
  3. IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

  • J Immunother Cancer. 2021 Jun;9(6):e002722. doi: 10.1136/jitc-2021-002722.
Qi Wu 1 2 3,  Ai-Ling Tian 2 3 4,  Bei Li 5,  Marion Leduc 2 3,  Sabrina Forveille 2 3,  Peter Hamley 6,  Warren Galloway 6,  Wei Xie 2 3,  Peng Liu 2 3,  Liwei Zhao 2 3,  Shuai Zhang 2 3 4,  Pan Hui 2 3 4,  Frank Madeo 7 8 9,  Yi Tu 10,  Oliver Kepp 11 3,  Guido Kroemer 11 3 12 13 14
Affiliations

Affiliations

  • 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 2 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
  • 3 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
  • 4 Faculty of Medicine, Université Paris Saclay, Kremlin Bicêtre, France.
  • 5 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 6 Samsara Therapeutics Ltd, Oxford, UK.
  • 7 Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
  • 8 BioTechMed-Graz, Graz, Austria.
  • 9 Field of Excellence BioHealth, University of Graz, Graz, Austria.
  • 10 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China [email protected] [email protected] [email protected].
  • 11 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France [email protected] [email protected] [email protected].
  • 12 Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, China.
  • 13 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 14 Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
PMID: 34127545 DOI: 10.1136/jitc-2021-002722
Abstract

Background: Pharmacological Autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel Autophagy inducers.

Results: Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active Akt serine/threonine kinase 1 (Akt1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast Cancer patients, the activating phosphorylation of IGF1R correlated with inhibited Autophagy, an unfavorable local immune profile, and poor prognosis.

Conclusion: Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of Cancer in conjunction with chemoimmunotherapies.

Keywords

breast neoplasms; immunotherapy; systems biology.

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