blood-cancer

AML leukemic stem cells depend on specific PI3K pathway—and combining PI3K + EZH inhibitors overcomes resistance.

Leukemic stem cells (LSCs) drive AML relapse by resisting treatments targeting bulk tumor cells. This study found LSCs are specifically dependent on the PI3K alpha isoform (P110α). When PI3K is inhibited in AML cells, a compensatory resistance mechanism emerges: EZH2 protein is downregulated, and…

AML leukemic stem cells depend on specific PI3K pathway—and combining PI3K + EZH inhibitors overcomes resistance.

Combining a PI3K inhibitor with a dual EZH1/2 inhibitor overcame this acquired resistance and achieved sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo.

This rational combination strategy directly addresses a clinically observed resistance mechanism and could be applicable to patients with relapsed/refractory AML.

Key Findings

LSCs are specifically dependent on the PI3K alpha (P110α) isoform
PI3K inhibition causes compensatory EZH2 downregulation and EZH1 upregulation as resistance mechanism
Combining PI3K inhibitor with dual EZH1/2 inhibitor overcomes resistance
Combination effective ex vivo and in murine AML + PDX models in vivo
Targets a non-genetic epigenetic resistance mechanism relevant to AML relapse

Implications

PI3K + EZH1/2 inhibitor combination addresses a specific, defined resistance mechanism in AML LSCs. This rational combination warrants clinical development, particularly for relapsed/refractory AML patients who have progressed on PI3K-targeted therapies.

Caveats

Preprint (bioRxiv); not yet peer-reviewed; abstract-only. Results are preclinical—clinical trials needed. EZH1/2 inhibitors have their own toxicity profiles. Generalizability to all AML subtypes requires investigation.

Source: bioRxiv — 2026-04-11

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AML leukemic stem cells depend on specific PI3K pathway—and combining PI3K + EZH inhibitors overcomes resistance.

Key Findings

Implications

Caveats

Read more

Landmark DCIS trial, CRC microbiome & AML combos

Colorectal Cancer Microbiome Discovery Platform

GBM Tumor Microenvironment Drug Target Atlas

BET Inhibitor Target Selectivity Database