Scientists from Shanghai Institute of Materia Medica (SIMM), CAS made progresses in discovering the role of the metabolic enzyme phosphoglycerate mutase 1 (PGAM1) in maintaining genomic stability, and found that PGAM1 inhibitors have the potential to expand the therapeutic benefits of FDA-approved ovarian cancer Olaparib (Lynparza) to a wider range of cancer types than currently indicated, such as triple-negative breast cancer. The finding was published in the Journal of Cell Biology on January 25, 2017. 

Deregulated metabolism is a hallmark of cancer. Different from most normal differentiated cells, tumor cells tend to metabolize glucose via aerobic glycolysis. This rewired metabolism ensures the elevated requirements of cancer cells for the production of biomass, including fatty acids, amino acids, and nucleotides, to support unrestricted cell growth. PGAM1 is a glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate (3-PG) into 2-phosphoglycerate (2-PG) in glycolysis. By converting 3-PG into 2-PG, PGAM1 also functions to stimulate pentose phosphate pathway (PPP) and serine generation. This unique position in metabolic network makes PGAM1 an attractive target for anticancer therapy. However, the therapeutic promise of PGAM1 in cancer remains to be better defined. 

Researchers at the SIMM, CAS discovered that PGAM1 inhibition resulted in a defect in the synthesis of deoxynucleotide triphosphates (dNTPs) – the building blocks of DNA. This, in turn, activated a cellular stress that degraded CtIP, a protein required for homologous recombination repair, an essential repair pathway specifically repairing double-stranded lesions of genomic DNA. In this way, PGAM1 inhibition shuts down the power supply for DNA repair in cancer cells and cells gain a phenotypic change called “BRCAness”, which mimics mutation of tumor suppressor genes BRAC1/2 in sporadic cancer. 

These findings in turn reveal a therapeutic indication for PGAM1 inhibitors, as cancers carrying BRCA1 and BRCA2 mutations are known to exhibit susceptibility to poly ADP ribose polymerase (PARP) inhibitor Olaparib, which was approved by the FDA in 2014 to treat ovarian cancers with BRCA mutations. In this study, the researchers have shown that combination with a PGAM1 inhibitor (PGAMI-004A) to impair homologous recombination repair sensitizes triple-negative breast cancers containing functional BRCA1 and BRCA2 genes to Olaparib. This study may provide a therapeutic solution for triple-negative cancers that currently lack effective therapies and reveal a potential therapeutic opportunity for PGAM1 inhibitors. 

This work was supported by the China International Science and Technology Cooperation Program, the National Science and Technology Major Project, the Strategic Priority Research Program of the Chinese Academy of Sciences, the Natural Science Foundation of China for Innovation Research Group, and grants from the Natural Science Foundation of China. 

Full text link: http://jcb.rupress.org/content/early/2017/01/24/jcb.201607008 

Spotlight comment link: http://jcb.rupress.org/content/216/2/295 

Figure：PGAM1 inhibition sensitizes triple-negative breast cancer xenograft models to Olaparib(Left); A schematic model showing the role of PGAM1 in promoting homologous recombination repair in responding to genomic stress(Right). (Image by SIMM)  

Key words: 

Phosphoglycerate mutase 1, homologous recombination repair, poly ADP ribose polymerase (PARP) inhibitors 

Corresponding authors: 

HUANG Min and DING Jian 

Shanghai Institute of Materia Medica, CAS 

Email: mhuang@simm.ac.cn, jding@simm.ac.cn 

(Credit: HUANG Min; Editor: PAN Peihua)