Contribution of serine synthesis enzyme PSPH in the pathogenesis and therapeutic resistance of T-ALL

Cancer cells rewire their energy metabolism during tumorigenesis. My host lab recently showed that the majority of T-cell acute lymphoblastic leukemia (T-ALL) samples overexpress serine/glycine synthesis enzymes and that these leukemic cells depend on this pathway for cancer progression. Whereas non-malignant cells typically take up serine and glycine from their environment and will not synthesize it themselves, some cancer cells activate this endogenous serine/glycine synthesis pathway to feed their high requirements of generating ATP, purines, lipids, reductive equivalents to control redox homeostasis and α- ketoglutarate to regulate DNA demethylation. From this perspective, it is essential to discover genetic drivers of the serine/glycine pathway allowing us to stratify patients for adjuvant therapeutic targeting of the serine/glycine pathway. The ribosomal RPL10 R98S mutation induces serine/glycine synthesis addiction in T-ALL, but other mechanisms remain unknown. We aimed at delineating additional genetic defects underlying serine/glycine synthesis addiction in leukemia and solid cancers.           

RNA-Seq analysis revealed that T-ALL, lung adenocarcinoma (LUAD) and neuroendocrine prostate cancer patients with overexpression of transcription factor NKX2-1 show significantly increased expression of serine/glycine synthesis enzymes. We confirmed binding of NKX2-1 to the promoter and enhancer regions of serine synthesis enzyme genes in lung cancer and T-ALL and showed that NKX2-1 overexpression increases mRNA and protein expression levels of serine/glycine synthesis enzymes up to 3-fold in cancer cell lines. Furthermore, NKX2-1 overexpression enabled cancer cells to proliferate upon limited serine/glycine availability and this was abrogated by knocking down PSPH. Metabolic profiling revealed that NKX2-1 driven serine/glycine synthesis was used to generate ATP, glutathione and nucleotides. Accordingly, NKX2-1 lung tumor-bearing mice showed elevated glutathione serum levels. Moreover, we could show that NKX2-1 expressing cells have an altered lipidome and methylome. Lastly, similar to known serine/glycine dependent cancer models, NKX2-1 cancer cells are sensitive to the repurposed serine/glycine synthesis targeting drug sertraline and topoisomerase inhibitor etoposide. Conformingly, while NKX2-1 positive LUAD is associated with early disease progression, etoposide treated patients with high NKX2-1 expression present improved outcomes. We identify NKX2-1 as a novel oncogenic transcription factor driving overexpression of serine/glycine synthesis enzymes in cancer. Our data support that NKX2-1 positive cancers depend on serine/glycine synthesis for their proliferation and survival. Hence, this pathway represents a novel therapeutic vulnerability in NKX2-1 positive cancers.

Following these findings and given the observation that the serine/glycine synthesis pathway can act as a drug resistance mechanism in multiple cancer subtypes, we tested the potential of the antidepressant sertraline in combination therapy in vitro in T-ALL cell lines. We found that sertraline acts synergistically with proteasome and histone deacetylase inhibitors in vitro in cancer cell lines, but additional in vivo experiments in animal models are required to validate these findings.