Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 Mar 2024
20 Mar 2024
Historique:
received:
02
08
2023
accepted:
11
03
2024
medline:
22
3
2024
pubmed:
21
3
2024
entrez:
21
3
2024
Statut:
epublish
Résumé
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.
Identifiants
pubmed: 38509064
doi: 10.1038/s41467-024-46811-w
pii: 10.1038/s41467-024-46811-w
pmc: PMC10954758
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Protein Kinase Inhibitors
0
Mitogen-Activated Protein Kinases
EC 2.7.11.24
KRAS protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2503Subventions
Organisme : NCI NIH HHS
ID : U01 CA284086
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244938
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262506
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA272213
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA274318
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248917
Pays : United States
Informations de copyright
© 2024. The Author(s).
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