DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

Sk. Kayum Alam, Yongchang Zhang, Li Wang, Zhu Zhu, Christina E. Hernandez, Yuling Zhou, Nong Yang, Jian Lei, Xiaoyan Chen, Liang Zeng, Mark A Klein, Luke H. Hoeppner

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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 EGFR:ERBB3 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.

Original languageEnglish (US)
Pages (from-to)83-98
Number of pages16
JournalOncogene
Volume41
Issue number1
Early online dateOct 21 2021
DOIs
StatePublished - Jan 3 2022

Bibliographical note

Funding Information:
This work was supported by The Elsa U. Pardee Foundation, Institutional Research Grant #129819-IRG-16-189-58-IRG81 from the American Cancer Society, and The Hormel Foundation (to L.H.H.) as well as the Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award (to S.K.A.). This material is based partially upon work supported by the Department of Veterans Affairs (specifically, the Veterans Health Administration). M.A.K. is an employee of the Minneapolis VA Healthcare System.

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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