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

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.

• Authors: Qi Wu, Ai-Ling Tian, Bei Li, Marion Leduc, Sabrina Forveille, Peter Hamley, Warren Galloway, Wei Xie, Peng Liu, Liwei Zhao, Shuai Zhang, Pan Hui, Frank Madeo, Yi Tu, Oliver Kepp, Guido Kroemer
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 6 (06 2021) ISSN: 2051-1426 [Electronic] England
• PMID: 34127545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antineoplastic Agents
• Receptor, IGF Type 1

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Autophagy (genetics)
• Female
• Humans
• Mice
• Receptor, IGF Type 1 (antagonists & inhibitors)