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mTORi unlocks AML resistance to LSD1i
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Figure 5. Inhibiting insulin receptor substrate 1 sensitizes resistant acute myeloid leukemia cells to LSD1 inhibition. (A) Relative cell number of NB4 cells treated with either vehicle (Veh), DDP38003 (DDP, 0.5 mM), NT-157 (1.25 mM) or their combination for 72 hours (h). Data were statistically analyzed using one way ANOVA followed by Bonferrroni post hoc test (n=3). *:P<0.05. (C) Relative cell number of THP-1 cells treated with either vehi- cle (Veh), DDP38003 (DDP, 0.5 mM), NT-157 (1.25 mM) or their combina- tion for 24 h. Data were statistically analyzed using one way ANOVA fol- lowed by Bonferrroni post-hoc test (n=3).*: P<0.05. (B) Western blot analysis of THP-1 cells treated as indicated. Vinculin served as a load- ing control. (D-E) Relative cell num- ber of NB4 (D) and THP-1 (F) cells treated with either vehicle (Veh), DDP38003 (DDP, 0.5 mM), all-trans- retinoic acid (ATRA – 1 mM) or their combination. Data were statistically analyzed using one way ANOVA fol- lowed by Bonferrroni post hoc test (n=3).*: P<0.05. (E) Western blot analysis. Vinculin served as a load- ing control.
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who demonstrated that heightened mTORC1 activity promotes glycolysis and drives glucose addiction in AML cells.38 Since mTOR acts as a fundamental metabolic checkpoint, LSD1-induced mTOR modulation might con- tribute to the epigenetic plasticity of cancer cell metabo- lism.11 The ON/OFF regulatory effects of LSD1i on mTOR could also account for the previously reported regulatory effects of LSD1 on metabolic reprogramming.39,40
Importantly, co-inhibiting LSD1 and mTOR significant- ly reduced the leukemic burden and prolonged the sur- vival of mice xenotransplanted with primary patient- derived AML (with MLL-AF9 chromosomal transloca- tions) compared to monotherapies. Consistent with the preclinically observed synergy between HDAC inhibitors and mTOR inhibitors, encouraging anticancer activities of vorinostat (HDAC inhibitor) when combined with sirolimus (mTOR inhibitor) have also been reported in patients with refractory Hodgkin lymphoma, perivascular
epithelioid tumor, and hepatocellular carcinoma.36,41 The observed synergy between LSD1i and mTOR inhibitors remains to be verified in patient-derived AML blasts exhibiting a diverse genetic background.
In addition, it is worth mentioning that while we have not noticed any potential impact of LSD1 inhibition on the proliferation as well as mTOR signaling of primary human CD34+ cord blood cells following three days of treatment, this does not exclude potential adverse effects on normal hematopoiesis following long-term LSD1 inhi- bition which was previously reported.42 Hence, this should carefully be considered while designing clinical trials eval- uating the efficacy of LSD1i as a monotherapy or in com- bination regimens.
Acquired resistance is a frequently encountered hurdle in cancer therapy. Despite being formerly responsive, tumor cells have a formidable capability to develop resist- ance to indefinite spectra of anti-cancer agents when chal-
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