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Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases
Lillian R Klug1, Jason D Kent1, Michael C Heinrich1
1Portland VA Health Care System, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA.
Abstract:
Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation. Recently, type I TKIs, which can bind to active kinase conformations, have been developed with specificity for class III RTK members. Some type I TKIs, such as crenolanib and avapritinib (BLU-285), have entered clinical studies for patients with activation loop mutations in KIT, PDGFRA, or FLT3. Preliminary results suggest that these type I TKIs show activity in these patient populations that previously lacked effective treatments. This article reviews the inactive and active structures of KIT, PDGFRA, and FLT3, how the mutations seen in human cancers affect kinase structure, and the clinical implications of these mutations in terms of type I vs. type II TKI binding.
Insights
Mutations in class III receptor tyrosine kinases (RTKs) like KIT, PDGFRA, and FLT3 cause resistance to type II inhibitors. New type I inhibitors show promise for treating these resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Class III receptor tyrosine kinases (RTKs), including KIT, PDGFRA, and FLT3, are frequently mutated in human cancers.
- Activation loop mutations in these RTKs lead to constitutive activation and resistance to currently available type II tyrosine kinase inhibitors (TKIs) like imatinib and sunitinib.
- These mutations destabilize inactive kinase conformations, shifting the equilibrium towards active states, rendering type II TKIs ineffective.
Purpose of the Study:
- To review the structural basis of class III RTK activation and the impact of oncogenic mutations.
- To discuss the differential binding mechanisms of type I and type II TKIs to class III RTKs.
- To highlight the clinical potential of type I TKIs in patients with resistant RTK mutations.
Main Methods:
- Structural analysis of inactive and active conformations of KIT, PDGFRA, and FLT3.
- Review of literature on activation loop mutations in class III RTKs and their effect on kinase structure.
- Analysis of clinical data for type I TKIs targeting mutated class III RTKs.
Main Results:
- Activation loop mutations in KIT, PDGFRA, and FLT3 promote an active kinase conformation.
- Type II TKIs bind to inactive conformations and are ineffective against these mutations.
- Type I TKIs are designed to bind active conformations and have shown preliminary efficacy in clinical studies.
- Crenolanib and avapritinib (BLU-285) are examples of type I TKIs in clinical development.
Conclusions:
- Understanding the structural impact of RTK mutations is crucial for developing targeted therapies.
- Type I TKIs represent a promising therapeutic strategy for patients with cancers driven by activated class III RTK mutations.
- Further clinical investigation of type I TKIs is warranted for previously untreatable patient populations.
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