IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms
Open Access
- 14 June 2021
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 9 (6), e002722
- https://doi.org/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
Funding Information
- Association pour la Recherche sur le Cancer
- BioTechMed
- University of Graz (Fast4Health)
- Université Paris-Saclay, Plateforme Imagerie
- Ile de France (DIM Elicit)
- Ligue Contre le Cancer
- Natural Science Foundation of Hubei Province (2020CFA026)
- Agence national de la recherche (Projets blancs)
- European Union
- Fondation pour la Recherche Médicale
- High-end Foreign Expert Program in China (GDW20171100085)
- Fondation Carrefour
- IdEx Université de Paris ANR (18-IDEX-0001)
- Labex (ANR-18-IDEX-0001)
- Austrian Federal Ministry of Education, Science and Research (BMWFW-80.109/0001-WF/V/3b/2015))
- Austrian Science Fund (W1226, P27893, P29203,P29262,P31727, SFB LIPOTOX F3007 & F3012)
- Chinese Scholarship Council
- AMMICA (US23/CNRS UMS3655)
- Association Ruban Rose
- Cancéropôle Ile de France
- Elior
- Equipex Onco-Pheno-Screen
- European Joint Program on Rare Disease
- Gustave Roussy (Odyssea)
- European Union Horizon 2020 Projects (Oncobiome and Crimson)
- Fondation Carrefour
- Institut National Du Cancer
- Inserm
- Institut Universitaire de France
- RHU Torino Lumière
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination
- SIRIC Cancer Research and Personalized Medicine
- NAWI Granz (BioHealth)
- BioTechMed-Graz (EPIAge)
This publication has 64 references indexed in Scilit:
- Cytoplasmic STAT3 Represses Autophagy by Inhibiting PKR ActivityMolecular Cell, 2012
- Autophagy modulation as a potential therapeutic target for diverse diseasesNature Reviews Drug Discovery, 2012
- Starvation, detoxification, and multidrug resistance in cancer therapyDrug Resistance Updates, 2012
- Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagyCardiovascular Research, 2011
- Autophagy and the Integrated Stress ResponseMolecular Cell, 2010
- The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membraneCell Death & Differentiation, 2010
- Extending Healthy Life Span—From Yeast to HumansScience, 2010
- Clinical Significance of Insulin-Like Growth Factor Type 1 Receptor and Epidermal Growth Factor Receptor in Patients with Advanced Gastric CancerOncology, 2008
- Effect of IGF‐1 on the balance between autophagy of dysfunctional mitochondria and apoptosisFEBS Letters, 2004
- Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell GrowthCancer Research, 2004