Acute myeloid leukemia (AML) is characterized by abnormal phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR [PAM]) pathway activity, which is accompanied by suppressed retinoic acid signaling and results in increased proliferation and differentiation blockade of immature myeloid cells. It had been demonstrated that mixed-lineage leukemia-rearranged AML was notably affected by PAM pathway inhibition. For a study, researchers aimed to test a combination approach combining all-trans retinoic acid (ATRA) and small molecule inhibitors of the PAM signaling pathway to target a wider range of various AML subtypes.

They discovered that PI3K(ZSTK474), mTOR (WYE132), or PI3K/mTOR (BEZ235, dactolisib) inhibition in conjunction with ATRA therapy significantly lowered the protein levels of the proto-oncogene MYC. In conjunction with BEZ235, ATRA therapy resulted in G1 arrest, loss of clonal ability, virtually total eradication of cellular MYC, and terminal granulocytic differentiation. They showed that PAM inhibitors and ATRA therapy target MYC in different ways. ATRA decreases MYC’s production, resulting in its phosphorylation at threonine 58 by glycogen synthase kinase 3 beta and subsequent destruction when the PAM route is inhibited.

They outlined a strategy combining several well-known medications to lower aberrant MYC levels synergistically, effectively preventing proliferation and promoting differentiation in a variety of AML subtypes.