Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer
Abstract Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cel...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2022-03-01
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| Series: | Molecular Biomedicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43556-022-00070-7 |
| _version_ | 1819177111625138176 |
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| author | Hang Ruan Brian J. Leibowitz Yingpeng Peng Lin Shen Lujia Chen Charlie Kuang Robert E. Schoen Xinghua Lu Lin Zhang Jian Yu |
| author_facet | Hang Ruan Brian J. Leibowitz Yingpeng Peng Lin Shen Lujia Chen Charlie Kuang Robert E. Schoen Xinghua Lu Lin Zhang Jian Yu |
| author_sort | Hang Ruan |
| collection | DOAJ |
| description | Abstract Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cells. Mechanistically, the combination, not single agent, rapidly depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2α-dependent cell death through the activation of extrinsic and intrinsic apoptotic pathways. Cell death is selectively induced in mutant KRAS CRC cells with elevated basal Myc and p-eIF2α and is characterized by CHOP induction and transcriptional signatures in proteotoxicity, oxidative stress, metabolic inhibition, and immune activation. BR-induced p-GCN2/p-eIF2α elevation and cell death are strongly attenuated by MYC knockdown and enhanced by MYC overexpression. The BR combination is efficacious against mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by inducing p-eIF2α/CHOP and cell death. Interestingly, an elevated four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked to shortened overall survival in CRC patients. These data support that Myc-dependent stress adaptation drives the progression of mutant KRAS CRC and serves as a therapeutic vulnerability, which can be targeted using dual translational inhibitors. |
| first_indexed | 2024-12-22T21:21:28Z |
| format | Article |
| id | doaj.art-897eff7e4d3547fe9e1e5347bbb62633 |
| institution | Directory Open Access Journal |
| issn | 2662-8651 |
| language | English |
| last_indexed | 2024-12-22T21:21:28Z |
| publishDate | 2022-03-01 |
| publisher | Springer |
| record_format | Article |
| series | Molecular Biomedicine |
| spelling | doaj.art-897eff7e4d3547fe9e1e5347bbb626332022-12-21T18:12:12ZengSpringerMolecular Biomedicine2662-86512022-03-013111610.1186/s43556-022-00070-7Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancerHang Ruan0Brian J. Leibowitz1Yingpeng Peng2Lin Shen3Lujia Chen4Charlie Kuang5Robert E. Schoen6Xinghua Lu7Lin Zhang8Jian Yu9UPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionUPMC Hillman Cancer Center Research PavilionAbstract Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cells. Mechanistically, the combination, not single agent, rapidly depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2α-dependent cell death through the activation of extrinsic and intrinsic apoptotic pathways. Cell death is selectively induced in mutant KRAS CRC cells with elevated basal Myc and p-eIF2α and is characterized by CHOP induction and transcriptional signatures in proteotoxicity, oxidative stress, metabolic inhibition, and immune activation. BR-induced p-GCN2/p-eIF2α elevation and cell death are strongly attenuated by MYC knockdown and enhanced by MYC overexpression. The BR combination is efficacious against mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by inducing p-eIF2α/CHOP and cell death. Interestingly, an elevated four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked to shortened overall survival in CRC patients. These data support that Myc-dependent stress adaptation drives the progression of mutant KRAS CRC and serves as a therapeutic vulnerability, which can be targeted using dual translational inhibitors.https://doi.org/10.1186/s43556-022-00070-7Mutant KRASMyceIF2αColorectal cancerEverolimusBortezomib |
| spellingShingle | Hang Ruan Brian J. Leibowitz Yingpeng Peng Lin Shen Lujia Chen Charlie Kuang Robert E. Schoen Xinghua Lu Lin Zhang Jian Yu Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer Molecular Biomedicine Mutant KRAS Myc eIF2α Colorectal cancer Everolimus Bortezomib |
| title | Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer |
| title_full | Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer |
| title_fullStr | Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer |
| title_full_unstemmed | Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer |
| title_short | Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer |
| title_sort | targeting myc driven stress vulnerability in mutant kras colorectal cancer |
| topic | Mutant KRAS Myc eIF2α Colorectal cancer Everolimus Bortezomib |
| url | https://doi.org/10.1186/s43556-022-00070-7 |
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