Identification of a novel metabolic-related mutation (<i>IDH1</i>) in metastatic pancreatic cancer

Brody, Jonathan R.; Yabar, Cinthya S.; Zarei, Mahsa; Bender, Joseph; Matrisian, Lynn M.; Rahib, Lola; Heartwell, Craig; Mason, Kimberly; Yeo, Charles J.; Peiper, Stephen C.; Jiang, Wei; Varieur, Katelyn; Madhavan, Subha; Petricoin, Emanuel; Fortuna, Danielle; Curtis, Mark; Wang, Zi Xuan; Pishvaian, Michael J.; Winter, Jordan M.

doi:10.1080/15384047.2016.1210743

Cited by 18 publications

(39 citation statements)

References 39 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IDH1 has been the subject of numerous studies in the cancer research field because of its high mutation frequency in many cancers (36). Of note, this genetic abnormality is exceptionally rare in PDAC, and has only recently been reported in a single case by our group (37). We theorize that the rarity of this mutation in PDAC is related to the deleterious effect that has been ascribed to haploinsufficiency of the wild type allele under very austere conditions (38).…”

Section: Discussionmentioning

confidence: 54%

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer.

show abstract

Section: Discussionmentioning

confidence: 54%

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, we recently demonstrated that pancreatic cancers, which do not have IDH1 mutations, rely on WT.IDH1 expression to generate reductive power needed to combat severe oxidative stress ubiquitously present in the tumor microenvironment (11,25). For this reason, our group has postulated that IDH1 mutations may even be deleterious in pancreatic cancer due to the characteristically harsh microenvironment (16) and could account for the rarity of this genetic alteration in that lethal cancer (3). Others have shown the importance of WT.IDH1 for reductive carboxylation and lipogenesis under hypoxic conditions in other IDH1 wild-type cancers (e.g., lung; refs.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that the RNA stability factor, HuR (ELAVL1), regulates WT.IDH1 transcript expression in pancreatic cancer (which do not typically acquire IDH1 mutations; ref. 16). Mechanistically, the RNA-binding protein affects mRNA expression by first recognizing and binding AU-rich RNA elements within specific mRNA 3 0 untranslated regions (3 0 UTR; ref.…”

Section: Introductionmentioning

confidence: 99%

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

Zarei

Lal

Vaziri‐Gohar

et al. 2019

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of a-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. Implications: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

show abstract

“…Additional highly actionable altered genes included receptor tyrosine kinases (RTK), including activating mutations in ERBB2 (17, 2.8%) and several oncogenic fusions: CCDC6-RET, NCOA4-RET, STRN-ALK, LMNA-NTRK1, and ETV6-NTRK3. Three activating mutations in codon 132 of IDH1 were also observed (22).…”

Section: Genomic Alterations Detected By Ngsmentioning

confidence: 97%

Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative

Pishvaian

Bender²,

Halverson³

et al. 2018

Clinical Cancer Research

Self Cite

177

146

View full text Add to dashboard Cite

To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies. Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments-accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling. Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes ( or mutations, 8.4%) and cell-cycle genes ( or alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy ( = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [ = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24-0.94; = 0.03]. A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. .

show abstract

Identification of a novel metabolic-related mutation (IDH1) in metastatic pancreatic cancer

Cited by 18 publications

References 39 publications

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer

Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative

Contact Info

Product

Resources

About