Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells

Özcan, Selahattin Can; Mutlu, Aydan; Altunok, Tugba Hazal; Gurpinar, Yunus; Sarioglu, Aybike; Guler, Sabire; Muchut, Robertino J.; Iglesias, Alberto A.; Çelikler, Serap; Campbell, Paul M.; Yalçin, Ali

doi:10.1016/j.bbrc.2021.07.070

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…Our study showed that PFKFB3 was differentially expressed in a cancer-dependent manner, that is, it was highly expressed in seven types of cancers, while it was less expressed in 10 types of cancers, which was partially con rmed by IHC. The results for PAAD (42)(43)(44), COAD (45,46), STAD (47), HNSC (14,48,49), and THCA (50) were consistent with those of a previous study. The differential expression of PFKFB3 in KIRC, KICH, and KIRP was also consistent with a previous study by Li et al (51).…”

Section: Discussionsupporting

confidence: 91%

Systematic pan-cancer analysis identifies 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) as a biomarker of tumor invasion and metastasis, immunity, and prognosis

Liu

Zhang

et al. 2023

Preprint

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6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a potent regulator of glycolysis in tumor cells, and high PFKFB3 expression is significantly associated with the invasion and metastasis of several tumors. However, there are no comprehensive reports on whether PFKFB3 promotes tumor invasion and its mechanism in different cancer types. In addition, there are no systematic reports on the effect of PFKFB3 on the stemness and immune infiltration ability of different tumors and on the survival rate of patients. Herein, we conducted a pan-cancer analysis of PFKFB3 with the aim of exploring the key cellular and molecular mechanisms regulating the pathogenesis and progression of human cancers, and propose potential strategies for the prevention and treatment of cancer by targeting PFKFB3. Using bioinformatics analysis and integrative exploration from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) databases, the differential expression of PFKFB3 or phosphorylated PFKFB3 and its correlation with tumor staging and stemness, survival prognosis, and immune invasion were extensively analyzed. The analysis showed differential expression of PFKFB3 in normal tissues and in various cancers. Increased PFKFB3 expression is positively correlated with the invasive ability and immune infiltration of 31 cancers and significantly affects the staging, stemness, prognosis, and survival rate of several cancers. Alterations in phosphorylated PFKFB3 and RNA modifications are also involved in the development and progression of various cancers. PFKFB3 is involved in multiple protein interactions and has complex molecular functions, such as ATP/ADP metabolic and glycolytic processes. Furthermore, PFKFB3 has a high mutation frequency, especially amplification, in multiple tumors. These findings highlight the significance of PFKFB3 in cancer progression, which might serve as a surrogate pan-cancer biomarker to predict the progression and outcome of cancers, as well as the invasion and immune infiltration of different cancers. Ethical compliance: This study did not involve any patient or animal samples and was approved by the academic committee of Tongji University.

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Section: Discussionsupporting

confidence: 91%

Systematic pan-cancer analysis identifies 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) as a biomarker of tumor invasion and metastasis, immunity, and prognosis

Liu

Zhang

et al. 2023

Preprint

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“…Evidence that PFKFB3 promotes tumorigenesis through hyperactivation of metabolism and can be targeted therapeutically to decrease the viability of KRAS-mutant pancreatic cells seems contradictory to the negative influence PFKFBB3 has on KRAS dependency in our model. However, this relationship may instead offer insight into a metabolic mechanism of resistance in KRAS-mutant cancers that is promoting survival independently of KRAS [ 54 , 55 ]. Future studies into specific features and related mechanisms within our model may further elucidate targetable vulnerabilities that can synergize with KRAS inhibitors and/or overcome mechanisms of resistance.…”

Section: Discussionmentioning

confidence: 99%

An integrated model for predicting KRAS dependency

et al. 2023

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The clinical approvals of KRAS G12C inhibitors have been a revolutionary advance in precision oncology, but response rates are often modest. To improve patient selection, we developed an integrated model to predict KRAS dependency. By integrating molecular profiles of a large panel of cell lines from the DEMETER2 dataset, we built a binary classifier to predict a tumor’s KRAS dependency. Monte Carlo cross validation via ElasticNet within the training set was used to compare model performance and to tune parameters α and λ. The final model was then applied to the validation set. We validated the model with genetic depletion assays and an external dataset of lung cancer cells treated with a G12C inhibitor. We then applied the model to several Cancer Genome Atlas (TCGA) datasets. The final “K20” model contains 20 features, including expression of 19 genes and KRAS mutation status. In the validation cohort, K20 had an AUC of 0.94 and accurately predicted KRAS dependency in both mutant and KRAS wild-type cell lines following genetic depletion. It was also highly predictive across an external dataset of lung cancer lines treated with KRAS G12C inhibition. When applied to TCGA datasets, specific subpopulations such as the invasive subtype in colorectal cancer and copy number high pancreatic adenocarcinoma were predicted to have higher KRAS dependency. The K20 model has simple yet robust predictive capabilities that may provide a useful tool to select patients with KRAS mutant tumors that are most likely to respond to direct KRAS inhibitors.

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“…Evidence that PFKFB3 promotes tumorigenesis through hyperactivation of metabolism and can be targeted therapeutically to decrease the viability of KRAS-mutant pancreatic cells seems contradictory to the negative influence PFKFBB3 has on KRAS dependency in our model. However, this relationship may instead offer insight into a metabolic mechanism of resistance in KRAS-mutant cancers that is promoting survival independently of KRAS (53,54). Future studies into specific features and related mechanisms within our model may further elucidate targetable vulnerabilities that can synergize with KRAS inhibitors and/or overcome mechanisms of resistance.…”

Section: Discussionmentioning

confidence: 99%

An integrated model for predicting KRAS dependency

Tsai

Chareddy

Price

et al. 2022

Preprint

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Background: The clinical approvals of KRAS G12C inhibitors has been a revolutionary advance in precision oncology, but response rates are often modest. To improve patient selection, we developed an integrated model to predict KRAS dependency. Methods and Findings: By integrating molecular profiles of a large panel of cell lines from the DEMETER2 dataset, we built a binary classifier to predict a tumor KRAS dependency. Monte Carlo cross validation via ElasticNet within the training set was used to compare model performance and to tune parameters. The final model was then applied to the validation set. We validated the model with genetic depletion assays and an external dataset of lung cancer cells treated with a G12C inhibitor. We then applied the model to several Cancer Genome Atlas (TCGA) datasets. The final K20 model contains 20 features, including expression of 19 genes and KRAS mutation status. In the validation cohort, K20 had an AUC of 0.94 and accurately predicted KRAS dependency in both mutant and KRAS wild-type cell lines following genetic depletion. It was also highly predictive across an external dataset of lung cancer lines treated with KRAS G12C inhibition. When applied to TCGA datasets, specific subpopulations such as the invasive subtype in colorectal cancer and copy number high pancreatic adenocarcinoma were predicted to have higher KRAS dependency. Conclusion: The K20 model has simple yet robust predictive capabilities that may provide a useful tool to select patients with KRAS mutant tumors that are most likely to respond to direct KRAS inhibitors.

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Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells

Cited by 9 publications

References 22 publications

Systematic pan-cancer analysis identifies 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) as a biomarker of tumor invasion and metastasis, immunity, and prognosis

Systematic pan-cancer analysis identifies 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) as a biomarker of tumor invasion and metastasis, immunity, and prognosis

An integrated model for predicting KRAS dependency

An integrated model for predicting KRAS dependency

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