The multifaceted landscape behind imatinib resistance in gastrointestinal stromal tumors (GISTs): A lesson from ripretinib.

Abstract

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas and the gold-standard treatment is represented by tyrosine kinase inhibitors (TKIs). Unfortunately, first-line treatment with the TKI imatinib usually promotes partial response or stable disease rather than a complete response, and resistance appears in most patients. Adaptive mechanisms are immediately relevant at the beginning of imatinib therapy, and they may represent the reason behind the low complete response rates observed in GISTs. Concurrently, resistant subclones can silently continue to grow or emerge de novo, becoming the most representative populations. Therefore, a slow evolution of the primary tumor gradually occurs during imatinib treatment, enriching heterogeneous imatinib resistant clonal subpopulations. The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. Although ripretinib has broad anti-KIT and -PDGFRA activity, it failed to overcome sunitinib as second-line treatment, suggesting that imatinib resistance is more multifaceted than initially thought. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as non-coding RNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.

• Authors: Aldo Di Vito, Gloria Ravegnini, Francesca Gorini, Trond Aasen, César Serrano, Eva Benuzzi, Emma Coschina, Sarah Monesmith, Fabiana Morroni, Sabrina Angelini, Patrizia Hrelia
• Journal: Pharmacology & therapeutics (Pharmacol Ther) Vol. 248 Pg. 108475 (08 2023) ISSN: 1879-016X [Electronic] England
• PMID: 37302758 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Imatinib Mesylate
• Sunitinib
• ripretinib
• Receptor Protein-Tyrosine Kinases
• Antineoplastic Agents
• Protein Kinase Inhibitors

Topics

• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Gastrointestinal Stromal Tumors (drug therapy, genetics, pathology)
• Sunitinib (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• Mutation
• Gastrointestinal Neoplasms (drug therapy, genetics, pathology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)