| Autor: |
Kartha, Nithya, Gianopulos, Jessica E., Schrank, Zachary, Cavender, Sarah M., Dobersch, Stephanie, Kynnap, Bryan D., Wallace-Povirk, Adrianne, Wladyka, Cynthia L., Santana, Juan F., Kim, Jaeseung C., Yu, Angela, Bridgwater, Caroline M., Fuchs, Kathrin, Dysinger, Sarah, Lampano, Aaron E., Notta, Faiyaz, Price, David H., Hsieh, Andrew C., Hingorani, Sunil R., Kugel, Sita |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 5/3/2023, Vol. 15 Issue 694, p1-16, 16p |
| Abstrakt: |
Pancreatic ductal adenocarcinoma (PDAC) is classified into two key subtypes, classical and basal, with basal PDAC predicting worse survival. Using in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDAC, we found that basal PDACs were uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9, and this sensitivity was recapitulated in the basal subtype of breast cancer. We showed in cell lines, PDXs, and publicly available patient datasets that basal PDAC was characterized by inactivation of the integrated stress response (ISR), which leads to a higher rate of global mRNA translation. Moreover, we identified the histone deacetylase sirtuin 6 (SIRT6) as a critical regulator of a constitutively active ISR. Using expression analysis, polysome sequencing, immunofluorescence, and cycloheximide chase experiments, we found that SIRT6 regulated protein stability by binding activating transcription factor 4 (ATF4) in nuclear speckles and protecting it from proteasomal degradation. In human PDAC cell lines and organoids as well as in murine PDAC genetically engineered mouse models where SIRT6 was deleted or down-regulated, we demonstrated that SIRT6 loss both defined the basal PDAC subtype and led to reduced ATF4 protein stability and a nonfunctional ISR, causing a marked vulnerability to CDK7 and CDK9 inhibitors. Thus, we have uncovered an important mechanism regulating a stress-induced transcriptional program that may be exploited with targeted therapies in particularly aggressive PDAC. Exploiting loss of the ISR in basal PDAC: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor survival, and better treatments are urgently required. Here, Kartha and colleagues identified that high sirtuin 6 (SIRT6) abundance defined classical PDAC and controlled activating transcription factor 4 (ATF4) by regulating its stability. ATF4 is known to control the integrated stress response (ISR), which is constitutively active in classical PDAC. The more aggressive basal subtype was characterized by low SIRT6 expression, leading to low ATF4 abundance and therefore poor activation of the ISR. This inability to launch the ISR rendered basal PDAC xenografts markedly sensitive to inhibition of cyclin-dependent kinase 7 (CDK7) and CDK9, suggesting a potential treatment avenue for this extremely aggressive subtype. —MN [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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