Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition

Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i. Strikingly, unlike sensitive leukemias, mTOR complex 1 (mTORC1) signaling was robustly triggered in resistant leukemias following LSD1 inhibition. Transcriptomic, chromatin immunoprecipitation and functional studies revealed that insulin receptor substrate 1(IRS1)/extracellular-signal regulated kinases (ERK1/2) signaling critically controls LSD1i induced mTORC1 activation. Notably, inhibiting mTOR unlocked the resistance of AML cell lines and primary patient-derived blasts to LSD1i both in vitro and in vivo. In conclusion, mTOR activation might act as a novel pro-survival mechanism of intrinsic as well as acquired resistance to LSD1i, and combination regimens co-targeting LSD1/mTOR could represent a rational approach in AML therapy.