Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Humans
Mice, SCID
Molecular Targeted Therapy
Multiple Myeloma
/ drug therapy
Mutation
/ drug effects
Neoplasm Recurrence, Local
/ drug therapy
Oligonucleotides, Antisense
/ pharmacology
Proto-Oncogene Proteins p21(ras)
/ genetics
Small Molecule Libraries
/ pharmacology
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
04 11 2021
04 11 2021
Historique:
received:
28
12
2020
accepted:
07
05
2021
pubmed:
3
6
2021
medline:
15
12
2021
entrez:
2
6
2021
Statut:
ppublish
Résumé
Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.
Identifiants
pubmed: 34077955
pii: S0006-4971(21)01155-1
doi: 10.1182/blood.2020010572
pmc: PMC9710471
doi:
Substances chimiques
Antineoplastic Agents
0
KRAS protein, human
0
Oligonucleotides, Antisense
0
Small Molecule Libraries
0
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1705-1720Subventions
Organisme : NCI NIH HHS
ID : K08 CA245100
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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