# Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Myeloid Leukemias

## TL;DR

This paper reviews how cancer cells in myeloid leukemias become resistant to tyrosine kinase inhibitors and the mechanisms behind this resistance.

## Contribution

The paper provides a comprehensive review of resistance mechanisms in CML and FLT3-mutated AML to guide future therapeutic strategies.

## Key findings

- In CML, resistance often arises from BCR::ABL1 kinase domain mutations and alternative signaling pathways like SIRT1 and JAK2-STAT5.
- In FLT3-mutated AML, resistance is driven by FLT3 mutations and activation of RAS/MAPK and IDH2 pathways.
- Epigenetic changes and clonal selection also contribute to resistance in both CML and AML.

## Abstract

Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML) and FLT3-mutated acute myeloid leukemia (AML), yet durable remissions are curtailed by the emergence of drug resistance. This review summarizes the principal mechanisms that underlie that resistance.

In CML, the most common mechanism is the development of point mutations in the BCR::ABL1 kinase domain (KD). Additional layers of resistance arise when imatinib, a substrate for the P-glycoprotein (P-gp) efflux pump, is shunted out of the intracellular space and when leukemic cells engage alternative signaling pathways such as the SIRT1 and JAK2-STAT5. Up-regulation of the WNT/β-catenin pathway and epigenetic changes such as HOXA4 and PDLIM4 promoter hypermethylation have likewise been linked to TKI resistance.

FLT3-mutated AML shows a parallel yet distinct pattern. One of the most common mechanisms of acquired resistance to FLT3 inhibitors is point mutations in FLT3 itself; the gatekeeper F691L, N676K and K429E substitutions cause resistance to clinically used FLT3 inhibitors. Resistance is also driven by activation of alternative signaling cascades: RAS/MAPK and IDH2-associated pathways frequently emerge and make FLT3 inhibition less effective. After initial therapy, clonal selection allows inhibitor-insensitive subclones to dominate, while bone-marrow stromal factors, high CYP3A4 activity together with FGF2/FGFR1-mediated MAPK signaling, protect blasts from FLT3 inhibitors.

It is important to study the mechanisms of resistance responsible for treatment failure to develop therapeutic strategies to overcome this resistance. This paper aims to review the important mechanisms of resistance to TKIs, both in CML and AML.