A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer.
Humans
Tumor Suppressor Protein p53
/ metabolism
Proto-Oncogene Proteins p21(ras)
/ genetics
Proto-Oncogene Proteins c-myc
/ metabolism
Cell Line, Tumor
Mutation
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Oncogenes
/ genetics
Neoplasms
/ genetics
Signal Transduction
/ drug effects
HSP70 Heat-Shock Proteins
Mitochondrial Proteins
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
31 Aug 2024
31 Aug 2024
Historique:
received:
07
02
2024
accepted:
31
07
2024
revised:
31
07
2024
medline:
1
9
2024
pubmed:
1
9
2024
entrez:
31
8
2024
Statut:
epublish
Résumé
The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.
Identifiants
pubmed: 39217152
doi: 10.1038/s41419-024-06965-3
pii: 10.1038/s41419-024-06965-3
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
KRAS protein, human
0
Proto-Oncogene Proteins c-myc
0
HSPA9 protein, human
0
MYC protein, human
0
TP53 protein, human
0
HSP70 Heat-Shock Proteins
0
Mitochondrial Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
638Subventions
Organisme : Narodowe Centrum Nauki (National Science Centre)
ID : 2017/26/E/NZ5/00663
Organisme : Servier (Laboratoires Servier)
ID : PTO/Servier oncology grant ed.2022/23
Organisme : Instytut Medycyny Doswiadczalnej i Klinicznej im. M. Mossakowskiego, Polskiej Akademii Nauk (Mossakowski Medical Research Centre, Polish Academy of Sciences)
ID : FBW-03/2021
Informations de copyright
© 2024. The Author(s).
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