Aberrant signaling by activated forms of PDGFR can be inhibited by tyrosine kinase inhibitors (TKIs). PDGF receptors are class III receptor tyrosine kinase receptors, also known as dual-switch. Dual-switch receptors are activated through a series of phosphorylation and conformational changes that move the receptor from the inactive form to the fully activated form. Type II TKIs bind to the inactive form of the receptor at a site adjacent to the ATP-binding cleft, while type I TKIs bind to the active form (reviewed in Roskoski, 2018; Klug et al, 2018).
Primary mutations in PDGRFA occur in the activation loop, with a minor fraction found in the juxtamembrane domain (reviewed in Roskoski, 2018; Klug et al, 2018). Juxtamembrane domain mutations affect an autoinhibitory loop, shifting the equilibrium of the receptor towards the activated state; despite this, however, juxtamembrane domain mutants remain predominantly in the inactive state and as such are susceptible to inhibition by type II TKIs. Activation loop mutations more strongly favor the active conformation of the receptor and are susceptible to inhibition by both type II and type I TKI. The most prevalent PDGFRA mutation, D842V, promotes the active conformation strongly enough to be resistant to type II TKIs (reviewed in Roskoski, 2018; Klug et al, 2018).