SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia

Abstract

Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate (THF), whose production by the enzyme DHFR is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme SHMT, whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target engagement with 13 C-serine tracing. As methotrexate is standard treatment for T-cell acute lymphoblastic leukemia (T-ALL), we explored the utility of SHIN2 in this disease. SHIN2 increases survival in NOTCH1-driven mouse primary T-ALL in vivo . Low dose methotrexate sensitizes Molt4 human T-ALL cells to SHIN2, and cells rendered methotrexate resistant in vitro show enhanced sensitivity to SHIN2. Finally, SHIN2 and methotrexate synergize in mouse primary T-ALL and in a human patient-derived xenograft in vivo , increasing survival. Thus, SHMT inhibition offers a complementary strategy in the treatment of T-ALL.

Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth

“…Because of the increasing number of identified cancer subsets that are addicted to serine/glycine synthesis, inhibitors that target this pathway are of great interest. Previously identified PHGDH and SHMT inhibitors did not reach clinical trials since they were not able to efficiently target serine/glycine synthesis in vivo or because they have only recently been developed (7,8,16,17,23).…”

“…This highlights the necessity to develop novel therapeutic intervention strategies for these cancers, specifically focusing on targeting serine/glycine synthesis. PHGDH and SHMT inhibitors have been identified but did not enter clinical trials due to unfavorable pharmacokinetic profiles or because they have only recently been developed (7,8,16,17).…”

Local production of lactate, ribose phosphate, and amino acids by human triple-negative breast cancer

“…56,57 The observation of strongly elevated serine and glycine synthesis in select intact human tumors argues for further efforts to pharmacologically target these pathways, perhaps using PHGDH expression and/or isotope tracing as a patient selection criterion. 56,58,59 ll We also observed TNBC synthesis of amino acids branching from the TCA cycle: aspartate; glutamate; glutamine; and proline (but not asparagine). Among the standard 20 amino acids, aspartate is the least abundant in the circulation, and its internal synthesis is accordingly a necessity.…”

Folate metabolism: a re-emerging therapeutic target in haematological cancers

“…What makes them attractive is that they do not require any folate transporters or intracellular polyglutamation. Since 2017, when Ducker et al [ 99 ] described the first pharmacological inhibitor of SHMT2/1, these inhibitors have shown promising results, especially in T-ALL leukaemia, as single agents but also in combination with MTX [ 97 , 98 ]. These encouraging results could have implications in other blood cancers like AML and MM where effective treatment options are limited; however, this still requires further investigation.…”

“…Vazquez et al [ 96 ] proposed that expression of mitochondrial 1C metabolism enzymes determine the response to MTX. On that note, García-Cañaveras et al [ 97 ] showed that a dual inhibitor of SHMT1/2, SHIN2, synergises with MTX both in vitro and in vivo. More specifically, as a single agent SHIN2 inhibited the proliferation of T-ALL cell lines and increased survival in NOTCH1-driven mouse T-ALL models.…”