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 journalArticlepeer-review

11 Citations (Scopus)

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

Bibliographical note

Funding Information:
The authors would like to thank Ji-Sun Kim and Dr. Keunok Jung for their experimental assistance with the manuscript. This work was supported by the National Research Foundation (NRF) Grant (2014M3C1A3051470 and 2016R1A2A2A05005108 to YSK and 2016R1A2B3016282 to BCC) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea.

Funding Information:
The authors would like to thank Ji-Sun Kim and Dr. Keunok Jung for their experimental assistance with the manuscript. This work was supported by the National Research Foundation (NRF) Grant ( 2014M3C1A3051470 and 2016R1A2A2A05005108 to YSK and 2016R1A2B3016282 to BCC) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea . Appendix A

Publisher Copyright:
© 2019 Elsevier B.V.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer'. Together they form a unique fingerprint.

Cite this