PHGDH (Phosphoglycerate Dehydrogenase)

P=N/A, N=100, Completed, West China Hospital

This paper systematically reviews the mechanisms underlying therapy-induced metabolic reprogramming in BRAF-mutant melanoma and explores potential combinatorial strategies that target these metabolic vulnerabilities alongside established melanoma therapies. Key metabolic targets with promising therapeutic potential identified include lysine-specific demethylase 1, oxidative phosphorylation components, phosphoglycerate dehydrogenase, indoleamine 2,3-dioxygenase 1 and lipid metabolism enzymes such as fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme a reductase.

Combining PHGDH inhibitors with PD-1/PD-L1 blockade significantly improves antitumor effects compared to individual treatments. These results identify PHGDH as an important PD-L1 regulator, reveal a critical noncanonical mechanism underlying PHGDH's oncogenic function, and propose a potential therapeutic strategy for cancers with PHGDH overexpression.

Clinically, enhanced PHGDH activity, elevated serine levels, and increased glutathione abundance are strongly associated with poor oxaliplatin response in GC patient cohorts, suggesting PHGDH as a potential predictive biomarker for chemotherapy resistance. Together, these findings delineate a WNK1-PHGDH-driven serine metabolic reprogramming axis that promotes redox adaptation and chemoresistance in GC, highlighting its dual value as a mechanistic driver and a therapeutic vulnerability in cancer treatment.

We have identified ENO2 and PHGDH as metabolic vulnerabilities induced by the 1p/19q co-deletion in oligodendrogliomas and [6,6'-2H]-glucose as a non-invasive tracer of early response to therapy.

Notably, these strategies have shown promising potential in reversing drug resistance to BRAF inhibitors, sorafenib, 5-fluorouracil (5-FU) and other agents, providing novel strategies for pan-cancer therapy. Through a systematic and comprehensive analysis of the multi-dimensional functions, heterogeneous regulation and roles in therapeutic resistance of the SSP across cancer types, this review aims to elucidate the conserved principles and cancer-specific characteristics of the SSP as a metabolic hub. Additionally, we discuss the prospects and unique challenges of precise intervention strategies targeting the SSP in overcoming tumor heterogeneity and drug resistance.

Combining ASNase with the clinically approved PARP inhibitor Olaparib enhances the antineoplastic effect of each monotherapy in vitro and in vivo. Moreover, this combination shows effectiveness in homologous recombination-proficient colorectal cancer cells, suggesting broader therapeutic potential. Overall, our study identifies tumor metabolic and genomic vulnerabilities induced by ASNase and supports a rational combination strategy using clinically approved drugs.

These results highlight dual-targeted disruption of serine availability as a promising therapeutic strategy to overcome chemotherapy resistance in ΔNp63α-driven LUSC. This study underscores the importance of lineage-specific metabolic dependencies as essential targets for precision oncology in NSCLC.

These findings demonstrate that acquired sorafenib resistance in HCC is associated with a stable NRF2-driven transcriptional and metabolic reprogramming that enhances antioxidant capacity, suppresses ferroptosis and promotes tumor cell survival. Targeting NRF2-regulated redox metabolism may therefore represent a promising strategy to overcome therapeutic resistance in HCC.

Therapeutic strategies targeting metabolic vulnerabilities-including SSP blockade, cholesterol homeostasis disruption, and ferroptosis induction-show synergistic effects with conventional agents like temozolomide. This review highlights the intertwined metabolic circuits in GBM and explores their translational potential as targets for precision therapy.

Notably, cancer-associated fibroblasts (CAFs) reprogrammed by ISR-activated cells, shifting from myCAF to iCAF phenotype with reduced collagen synthesis and glycine-to-serine conversion, produced serine and sustained tumor growth in amino acid-depleted environments. Our findings demonstrate the power of translatome profiling to reveal stable, drug-resistant PDA cell states and identify a targetable CAF-tumor metabolic symbiosis, opening new avenues for therapeutic intervention in this highly lethal malignancy.