Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway
Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for...
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doaj-16cff39c74954feaa55f9afe71d7a3b72021-07-11T11:05:12ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112711110.1038/s41419-021-03970-8Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathwayBingbing Dai0Jithesh J. Augustine1Ya’an Kang2David Roife3Xinqun Li4Jenying Deng5Lin Tan6Leona A. Rusling7John N. Weinstein8Philip L. Lorenzi9Michael P. Kim10Jason B. Fleming11Departments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteDepartments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartments of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteAbstract Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.https://doi.org/10.1038/s41419-021-03970-8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bingbing Dai Jithesh J. Augustine Ya’an Kang David Roife Xinqun Li Jenying Deng Lin Tan Leona A. Rusling John N. Weinstein Philip L. Lorenzi Michael P. Kim Jason B. Fleming |
spellingShingle |
Bingbing Dai Jithesh J. Augustine Ya’an Kang David Roife Xinqun Li Jenying Deng Lin Tan Leona A. Rusling John N. Weinstein Philip L. Lorenzi Michael P. Kim Jason B. Fleming Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway Cell Death and Disease |
author_facet |
Bingbing Dai Jithesh J. Augustine Ya’an Kang David Roife Xinqun Li Jenying Deng Lin Tan Leona A. Rusling John N. Weinstein Philip L. Lorenzi Michael P. Kim Jason B. Fleming |
author_sort |
Bingbing Dai |
title |
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
title_short |
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
title_full |
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
title_fullStr |
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
title_full_unstemmed |
Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
title_sort |
compound nsc84167 selectively targets nrf2-activated pancreatic cancer by inhibiting asparagine synthesis pathway |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-07-01 |
description |
Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers. |
url |
https://doi.org/10.1038/s41419-021-03970-8 |
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