Targeting a Lineage-Specific PI3K?/AKT Signaling Module in Acute Myeloid Leukemia Using a Heterobifunctional Degrader Molecule
Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in non-malignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue- and/or tumor-restricted expression. Here, we show that in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110??-PIK3R5/p101 axis blocks AKT signaling, compromises cell fitness, and sensitizes to established AML therapies. Importantly, we find that existing small molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term anti-leukemic effect. To address this concern, we developed a PROteolysis-TArgeting Chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary AML patient samples, and syngeneic mouse models. Overall design: MOLM14 and OCI-AML2 AML cell lines were treated for 24h with ARM-165, AZ-2 or DMSO. Cells were subsequently lysed, total RNA extracted and RNA-sequencing libraries were prepared using TruSeq Stranded mRNA LT Sample Prep Kit. Sequencing librarie were sequenced on Illumina NovaSeq 600 sequencer.