Sertraline Targets Serine/Glycine Synthesis Enzyme SHMT
Geeraerts et al. Page 50
Healthy cells typically take up serine and glycine from their environment. By contrast, several cancers are metabolically addicted to endogenous serine/glycine synthesis to sustain their proliferation. This dependence on serine/glycine synthesis in cancer thus offers an attractive drug target. Previously developed serine/glycine synthesis inhibitors did not pass clinical trials due to unfavorable pharmacokinetic profiles. By utilizing a drug repurposing screen, Geeraerts and colleagues found that the clinically used antidepressant sertraline inhibits serine/glycine synthesis enzyme SHMT and selectively suppresses proliferation of serine/glycine synthesis addicted cancer cells. Furthermore, simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism offers a novel treatment strategy for these cancers.
PIM Kinases Promote Resistance to Therapy
Toth et al. Page 3
PIM kinases are oncogenic serine/threonine kinases that control cellular metabolism, proliferation, and survival. Due to their commonality in many cancer subtypes, efforts have focused at inhibiting PIM kinases. In this review article, Toth and Warfel outline the known signaling pathways through which PIM kinase operates as well as the current efforts to inhibit their function. They detail the role of PIM kinases in resistance to therapies such as PI3K/mTOR and angiogenesis inhibitors and the role of PIM inhibition in overcoming these resistances.
HLA Polymorphisms Predict TFR in CML
Ureshino et al. Page 142
The determinants of treatment-free remission (TFR) remain elusive in chronic phase chronic myeloid leukemia (CML-CP). In this study, Ureshino and colleagues assess polymorphisms in killer immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) as well as NK cell activation status in seventy-six patients. Their analysis revealed three HLA polymorphisms associated with TFR and that NK cell activation status contributed to deep molecular response (DMR). Taken together, their results suggest DMR depends on NK cell activation status and T-cell–mediated immunity contributes to TFR in CML-CP patients.
Hsp90 Inhibition and PD-1 Blockade in PDAC
Zhang et al. Page 150
Fibrotic stroma limits the ability to treat pancreatic ductal adenocarcinoma (PDAC) and results from the interaction of tumor cells, immune cells, and pancreatic stellate cells (PSCs) or cancer associated fibroblasts (CAF). Zhang and colleagues sought to inhibit inflammatory signals through Hsp90 inhibition. The Hsp90 inhibitor XL888 decreased levels of IL6, limited PSC/CAF growth, and reduced alpha-SMA expression. XL888 synergized with anti-PD-1 therapy in subcutaneous Panc02 and orthotopic KPC Luc tumors. Therefore, Hsp90 can reduce PSC/CAF signaling and enhance anti-PD-1 blockade in PDAC.
- ©2021 American Association for Cancer Research.
Volume 20, Issue 1
