DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma.
Oncogene
; 41(1): 83-98, 2022 01.
Article
em En
| MEDLINE
| ID: mdl-34675407
ABSTRACT
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-refractory lung adenocarcinoma (LUAD) progression is a major clinical problem. New approaches to predict and prevent acquired resistance to EGFR TKIs are urgently needed. Here, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 (HER3) to EGFR to mediate switching from EGFR homodimers to EGFRERBB3 heterodimers to bypass EGFR TKI-mediated inhibition by potentiating ERBB3-dependent activation of oncogenic signaling. In paired LUAD patient-derived specimens before and after EGFR TKI-refractory disease progression, we reveal that DARPP-32 and kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired resistance. In mice, DARPP-32 ablation sensitizes gefitinib-resistant xenografts to EGFR TKIs, while DARPP-32 overexpression increases gefitinib-refractory LUAD progression in gefitinib-sensitive lung tumors. We introduce a DARPP-32-mediated, ERBB3-dependent mechanism the LUAD cells use to evade EGFR TKI-induced cell death, potentially paving the way for the development of therapies to better combat therapy-refractory LUAD progression.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptor ErbB-3
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Fosfoproteína 32 Regulada por cAMP e Dopamina
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Terapia de Alvo Molecular
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Adenocarcinoma de Pulmão
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article