Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib

Qi Wu; Ai-Ling Tian; Guido Kroemer; Oliver Kepp

doi:10.1080/15548627.2021.1936934

Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib

Autophagy. 2021 Aug;17(8):2046-2047. doi: 10.1080/15548627.2021.1936934. Epub 2021 Jun 10.

Authors

Qi Wu^{1

2

3}, Ai-Ling Tian^{2

3

4}, Guido Kroemer^{2

3

5

6

7}, Oliver Kepp^{2

3}

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, Institut Universitaire de France, Paris, France.
³ Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
⁴ Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France.
⁵ Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, China.
⁶ Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.
⁷ Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Induction of macroautophagy (hereafter termed autophagy) is a strategy to improve the outcome of antineoplastic therapies by facilitating the induction of immunogenic cancer cell death and the consequent immune recognition of malignant cells. We analyzed 65,000 distinct compounds by means of a phenotypic discovery platform for autophagy induction and identified the IGF1R (insulin like growth factor 1 receptor) inhibitor picropodophyllin (PPP) as a potent inducer of autophagic flux. We found that PPP acts on-target, as an inhibitor of the tyrosine kinase activity of IGF1R and enhances the release of adenosine triphosphate, ATP, from stressed and dying cancer cells in vitro, thereby improving the therapeutic efficacy of chemoimmunotherapy in cancer-bearing mice. This PPP effect was phenocopied by another IGF1R inhibitor, linsitinib. Moreover, in human triple-negative breast cancer, phosphorylation of IGF1R correlates with reduced autophagy, an unfavorable local immune profile and poor prognosis. In summary, IGF1R inhibition may constitute a novel strategy for the treatment of cancer in the context of chemoimmunotherapy.

Keywords: Anticancer immunity; biosensor; drug discovery; high-content screening; immunogenic cell death.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Autophagy / drug effects*
Cell Proliferation / drug effects
Humans
Imidazoles / pharmacology*
Podophyllotoxin / analogs & derivatives*
Podophyllotoxin / pharmacology
Protein Kinase Inhibitors / pharmacology
Pyrazines / pharmacology*
Receptor, IGF Type 1 / drug effects*
Receptor, IGF Type 1 / metabolism

Substances

3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
IGF1R protein, human
Imidazoles
Protein Kinase Inhibitors
Pyrazines
picropodophyllin
Receptor, IGF Type 1
Podophyllotoxin

Grants and funding

OK receives funding by the DIM ELICIT initiative of the Ile de France; GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).