Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.
Humans
Lung Neoplasms
/ drug therapy
Proto-Oncogene Proteins p21(ras)
/ genetics
Adenocarcinoma of Lung
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Mutation
Disease Progression
Mitogen-Activated Protein Kinase Kinases
/ genetics
Proto-Oncogene Proteins c-mdm2
/ genetics
Transcription Factors
/ genetics
Combination therapy
Lung adenocarcinoma
MDM2
TP53
Targeted therapy
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
14
03
2023
revised:
01
05
2023
accepted:
08
05
2023
pmc-release:
01
09
2024
medline:
22
8
2023
pubmed:
15
5
2023
entrez:
14
5
2023
Statut:
ppublish
Résumé
Although targeted therapies have revolutionized the therapeutic landscape of lung adenocarcinomas (LUADs), disease progression on single-agent targeted therapy against known oncogenic drivers is common, and therapeutic options after disease progression are limited. In patients with MDM2 amplification (MDM2amp) and a concurrent oncogenic driver alteration, we hypothesized that targeting of the tumor-suppressor pathway (by means of restoration of p53 using MDM2 inhibition) and simultaneous targeting of co-occurring MAPK oncogenic pathway might represent a more durably effective therapeutic strategy. We evaluated genomic next-generation sequencing data using the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets platform to nominate potential targets for combination therapy in LUAD. We investigated the small molecule MDM2 inhibitor milademetan in cell lines and patient-derived xenografts of LUAD with a known driver alteration and MDM2amp. Of 10,587 patient samples from 7121 patients with LUAD profiled by next-generation sequencing, 6% (410 of 7121) harbored MDM2amp. MDM2amp was significantly enriched among tumors with driver alterations in METex14 (36%, p < 0.001), EGFR (8%, p < 0.001), RET (12%, p < 0.01), and ALK (10%, p < 0.01). The combination of milademetan and the MEK inhibitor trametinib was synergistic in growth inhibition of ECLC5-GLx (TRIM33-RET/MDM2amp), LUAD12c (METex14/KRAS Combined MDM2/MEK inhibition was found to have efficacy across multiple patient-derived LUAD models harboring MDM2amp and concurrent oncogenic drivers. This combination, potentially applicable to LUADs with a wide variety of oncogenic driver mutations and kinase fusions activating the MAPK pathway, has evident clinical implications and will be investigated as part of a planned phase 1/2 clinical trial.
Identifiants
pubmed: 37182602
pii: S1556-0864(23)00553-1
doi: 10.1016/j.jtho.2023.05.007
pmc: PMC10524759
mid: NIHMS1902258
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Protein Kinase Inhibitors
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
TRIM33 protein, human
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1165-1183Subventions
Organisme : NCI NIH HHS
ID : P01 CA129243
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251591
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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