# Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics

## TL;DR

This study identifies a resistant cell population in AML and shows that combining midostaurin with SMAC mimetics can overcome resistance.

## Contribution

The study reveals a progenitor-like cell state driving midostaurin resistance and identifies a novel drug combination to target it.

## Key findings

- Midostaurin-resistant AML cells exhibit a progenitor-like CD38+CD45RA+ phenotype with altered signaling.
- Combining midostaurin with SMAC mimetics selectively targets resistant cells and restores apoptosis.
- Venetoclax combinations affect CD34hi cells differently, highlighting distinct vulnerabilities in AML subpopulations.

## Abstract

FLT3-mutated acute myeloid leukemia (AML) remains difficult to treat due to frequent resistance to FLT3 inhibitors like midostaurin. In this study, we observed a progenitor-like CD38+CD45RA+ leukemic cell population that may be associated with midostaurin resistance. Midostaurin-resistant cells display disrupted membrane architecture and a shift in signaling from STAT5 to PI3K/AKT, favoring survival over apoptosis. Functional drug testing was consistent with clinical response to midostaurin, and together with multi-omic profiling, including single-cell and proteomic analyses, indicated the presence and relevance of this resistant phenotype. Drug combination screening revealed that co-targeting with SMAC mimetics restores apoptotic competence and selectively depletes the resistant population when combined with midostaurin. In contrast, venetoclax combinations preferentially affected CD34hi cells, underscoring distinct subpopulation vulnerabilities. These findings may point to a biologically relevant mechanism underlying midostaurin resistance.