Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer.

Autor: Ruan H; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA., Leibowitz BJ; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA., Peng Y; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA., Shen L; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China., Chen L; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Medical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA., Kuang C; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA., Schoen RE; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.; Department of Epidemiology, University of Pittsburgh School of Public Health Pittsburgh, Pittsburgh, PA, 15213, USA., Lu X; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Medical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA., Zhang L; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA., Yu J; UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA. yuj2@upmc.edu.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. yuj2@upmc.edu.
Jazyk: angličtina
Zdroj: Molecular biomedicine [Mol Biomed] 2022 Mar 21; Vol. 3 (1), pp. 10. Date of Electronic Publication: 2022 Mar 21.
DOI: 10.1186/s43556-022-00070-7
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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