Resistance to targeted therapies: delving into FLT3 and IDH

Abstract

Recent advances in FLT3 and IDH targeted inhibition have improved response rates and overall survival in patients with mutations affecting these respective proteins. Despite this success, resistance mechanisms have arisen including mutations that disrupt inhibitor-target interaction, mutations impacting alternate pathways, and changes in the microenvironment. Here we review the role of these proteins in leukemogenesis, their respective inhibitors, mechanisms of resistance, and briefly ongoing studies aimed at overcoming resistance.

Fig. 1. FLT3 activation and inhibition.

A FLT3 ligand binds FLT3 receptor with phosphorylation of the juxtamembrane domain. The activation loop assuming an open configuration, resulting in the active conformation. After phosphorylation, the PI3K/Akt, the STAT5, and the MAPK pathways are activated with alterations in transcription. B Type 1 inhibitors bind the ATP binding side regardless of ITD (red juxtamembrane domain) or TKD (red activation loop) mutations. C The left side depicts type 2 inhibitor binding a protein with an ITD mutation (red juxtamembrane domain). Type 2 inhibitors bind the activation loop, stabilizing the inactive conformation. On the right side, the TKD mutation (red activation loop), shifts the activation loop into an open conformation. The type 2 inhibitor is unable to bind, permitting ATP binding. Figure created with Biorender.com.

Fig. 2. The impact of IDH mutations and IDH inhibition.

A Mutations of IDH occur at the active site, resulting in neomorphic activity. 2HG production results in hypermethylation, increased BCL2 expression, and altered metabolism. B IDH inhibitors function by stabilizing the open conformation, preventing catalytic activity. Figure created with Biorender.com.