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.
| Original language | English (US) |
|---|---|
| Journal | Pharmacology and Therapeutics |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Activation loop mutation
- Kinase inhibitor
- Kinase inhibitor resistance
- KIT
- PDGFRA
- Type I kinase inhibitor
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
Cite this
Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases. / Klug, Lillian R.; Kent, Jason D.; Heinrich, Michael.
In: Pharmacology and Therapeutics, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases
AU - Klug, Lillian R.
AU - Kent, Jason D.
AU - Heinrich, Michael
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Activation loop mutation
KW - Kinase inhibitor
KW - Kinase inhibitor resistance
KW - KIT
KW - PDGFRA
KW - Type I kinase inhibitor
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UR - http://www.scopus.com/inward/citedby.url?scp=85049335367&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2018.06.016
DO - 10.1016/j.pharmthera.2018.06.016
M3 - Article
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
SN - 0163-7258
ER -