Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer. (1st December 2019)

• Record Type: Journal Article
• Authors: Kim, Ye-Jin; Baek, Du-San; Lee, Seyoung; Park, Daechan; Kang, Han Na; Cho, Byoung Chul; Kim, Yong-Sung
• Is Part Of: Cancer letters. Volume 466(2019)
• Page Start: 23
• Page End: 34
• Publication Date: 2019-12-01
• Subjects: KRAS mutation -- Integrin β3 -- Bispecific antibody -- Cetuximab resistance -- EGFR/NRP1 dual-targeting; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.09.005
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The therapeutic targeting of oncogenic KRAS mutant-harboring (KRAS MUT ) 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 KRAS MUT NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRAS MUT NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-mediated ternary complex comprising NRP1–integrin β3–KRAS MUT and its downstream signaling of PI3K-Akt and RalB-TBK1 as a primary resistance mechanism of KRAS MUT 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 KRAS MUT 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 KRAS MUT NSCLC. Highlights: Integrin β3 is involved in the resistance of KRAS MUT NSCLCs to anti-EGFR cetuximab. Integrin β3 mediates the formation of a NRP1–integrin β3–KRAS MUT ternary complex. EGFR/NRP1 dual-targeting bispecific antibody, Ctx-TPP11, sensitizes KRAS MUT NSCLCs. Ctx-TPP11 attenuates the downstream signaling driven by the ternary complex. Ctx-TPP11 displays potent anti-tumor activity in KRAS MUT NSCLC PDX tumors.