Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer

Ye Jin Kim, Du San Baek, Seyoung Lee, Daechan Park, Han Na Kang, Byoung Chul Cho, Yong Sung Kim

Research output: Contribution to journalArticle

Abstract

The therapeutic targeting of oncogenic KRAS mutant-harboring (KRASMUT) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRASMUT NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRASMUT NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-mediated ternary complex comprising NRP1–integrin β3–KRASMUT and its downstream signaling of PI3K-Akt and RalB-TBK1 as a primary resistance mechanism of KRASMUT NSCLC to cetuximab treatment. Importantly, we demonstrate that the EGFR/NRP1 dual-targeting bispecific antibody, Ctx-TPP11, attenuates the downstream signaling driven by the ternary complex via the cellular co-internalization and degradation of the NRP1-coupled complex, resulting in the alleviation of cetuximab resistance in KRASMUT NSCLCs in vitro and in vivo, including patient-derived xenograft mouse models. Our study shows that the dual-targeting of EGFR and NRP1 with a bispecific antibody might be an effective therapeutic strategy for KRASMUT NSCLC.

Original languageEnglish
Pages (from-to)23-34
Number of pages12
JournalCancer Letters
Volume466
DOIs
Publication statusPublished - 2019 Dec 1

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Neuropilin-1
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Antibodies
Bispecific Antibodies
Integrins
Therapeutics
Phosphatidylinositol 3-Kinases
Heterografts
Mutation
Cetuximab
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Ye Jin ; Baek, Du San ; Lee, Seyoung ; Park, Daechan ; Kang, Han Na ; Cho, Byoung Chul ; Kim, Yong Sung. / Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer. In: Cancer Letters. 2019 ; Vol. 466. pp. 23-34.
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Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer. / Kim, Ye Jin; Baek, Du San; Lee, Seyoung; Park, Daechan; Kang, Han Na; Cho, Byoung Chul; Kim, Yong Sung.

In: Cancer Letters, Vol. 466, 01.12.2019, p. 23-34.

Research output: Contribution to journalArticle

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