The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux.

Abstract

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

• Authors: Bo Ni, Qing Li, Chun Zhuang, Peiqi Huang, Xiang Xia, Linxi Yang, Xinli Ma, Chen Huang, Wenyi Zhao, Lin Tu, Yanying Shen, Chunchao Zhu, Zizhen Zhang, Enhao Zhao, Ming Wang, Hui Cao
• Journal: Cancer letters (Cancer Lett) Vol. 535 Pg. 215639 (06 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35288241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• GFRA1 protein, human
• Glial Cell Line-Derived Neurotrophic Factor
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Imatinib Mesylate

Topics

• Antineoplastic Agents (therapeutic use)
• Autophagy
• Gastrointestinal Neoplasms (pathology)
• Gastrointestinal Stromal Tumors (drug therapy)
• Glial Cell Line-Derived Neurotrophic Factor (genetics)
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Prospective Studies