Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer
In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene <i>KRAS</i> and tumor suppressor <i>STK11</i> (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a prev...
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MDPI AG
2022-01-01
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| author | Hyunmin Lee Feng Cai Neil Kelekar Nipun K. Velupally Jiyeon Kim |
| author_facet | Hyunmin Lee Feng Cai Neil Kelekar Nipun K. Velupally Jiyeon Kim |
| author_sort | Hyunmin Lee |
| collection | DOAJ |
| description | In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene <i>KRAS</i> and tumor suppressor <i>STK11</i> (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine <i>KRAS/LKB1</i> co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of <i>KRAS/LKB1</i> co-mutants. Here, we found that <i>KRAS/LKB1</i> co-mutant cells also exhibit an increased dependence on <i>N</i>-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced <i>KRAS/LKB1</i> co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in <i>KRAS/LKB1</i> co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC. |
| first_indexed | 2024-03-10T03:45:19Z |
| format | Article |
| id | doaj.art-551e97a18d044eb88f2188d434792fec |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:45:19Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
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| spelling | doaj.art-551e97a18d044eb88f2188d434792fec2023-11-23T11:21:20ZengMDPI AGCells2073-44092022-01-0111117610.3390/cells11010176Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung CancerHyunmin Lee0Feng Cai1Neil Kelekar2Nipun K. Velupally3Jiyeon Kim4Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USAChildren’s Medical Center Research Institute, UT-Southwestern Medical Center, Dallas, TX 75390, USADepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USADepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USADepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USAIn non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene <i>KRAS</i> and tumor suppressor <i>STK11</i> (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine <i>KRAS/LKB1</i> co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of <i>KRAS/LKB1</i> co-mutants. Here, we found that <i>KRAS/LKB1</i> co-mutant cells also exhibit an increased dependence on <i>N</i>-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced <i>KRAS/LKB1</i> co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in <i>KRAS/LKB1</i> co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.https://www.mdpi.com/2073-4409/11/1/176cancer metabolismmetabolic vulnerabilitynon-small cell lung cancer<i>KRAS</i> and <i>LKB1</i> co-mutationsthe hexosamine biosynthesis pathwayglycosylation |
| spellingShingle | Hyunmin Lee Feng Cai Neil Kelekar Nipun K. Velupally Jiyeon Kim Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer Cells cancer metabolism metabolic vulnerability non-small cell lung cancer <i>KRAS</i> and <i>LKB1</i> co-mutations the hexosamine biosynthesis pathway glycosylation |
| title | Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer |
| title_full | Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer |
| title_fullStr | Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer |
| title_full_unstemmed | Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer |
| title_short | Targeting PGM3 as a Novel Therapeutic Strategy in <i>KRAS/LKB1</i> Co-Mutant Lung Cancer |
| title_sort | targeting pgm3 as a novel therapeutic strategy in i kras lkb1 i co mutant lung cancer |
| topic | cancer metabolism metabolic vulnerability non-small cell lung cancer <i>KRAS</i> and <i>LKB1</i> co-mutations the hexosamine biosynthesis pathway glycosylation |
| url | https://www.mdpi.com/2073-4409/11/1/176 |
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