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

Abstract

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.

Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1, a novel oncogene in AML

“…This hypothesis is supported by the evidence that various miRNAs can modulate GSE1 expression 31,32,46 . Alternatively, GSE1 downregulation could be caused by the block of its translational initiation 47 , in line with recent data showing that -in some cell lines-LSD1 inhibitors activate the mTOR signalling cascade 48,49 , which directly affects protein synthesis 50 .…”

Dendritic cell vaccine immunotherapy; the beginning of the end of cancer and COVID-19. A hypothesis

“…Cancer immunotherapy is one of the new approaches that is currently studied in an attempt to uncover new opportunities for better outcomes for cancer patients [1] , [2] . It is a newly added pillar of oncotherapy in addition to the conventional therapies, i.e., chemotherapy, surgery, and radiotherapy.…”

Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment

“…2D). In a follow-up experiment, LSD1i primed P31/Fuj cells to the effects of MEKi ( 34 , 35 )—that is, suppression of proliferation and induction of apoptosis—in a dose-dependent manner (Fig. 2E).…”

“…Thus, MEKi and LSD1i are unlikely to be of significant clinical utility as single agents in unselected AML patient populations. Targeting of LSD1 in conjunction with mTOR inhibitors has been shown to induce apoptosis and reduce viability of AML cells ( 34 , 35 ). Crucially, however, LSD1 and mTOR inhibitors were tested as a cotreatment in these studies, and the cells found to be susceptible are limited to specific subgroups of MLL AML.…”