Abstract 3989: Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung cancer
2018
We previously identified an oncogenic fusion gene involving the 5′ region of SLC3A2 and the 3′ region of NRG1 in a patient with invasive mucinous adenocarcinoma (IMA) of the lung. Here, we characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3, which lacks tyrosine kinase activity, with ERBB2 using immunofluorescence staining, FACS analysis, and immunoprecipitation. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth in vivo in a xenograft model through the downstream signaling pathways of PI3K-AKT and MAP kinase. siRNA specific for ERBB2 and ERBB3, pertuzumab (a monoclonal antibody for ERBB2), lumretuzumab (a monoclonal antibody for ERBB3), and afatinib (an ERBB2 kinase inhibitor) all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or apatinib decreased tumor volume and weight, whereas combination treatment with these drugs and paclitaxel enhanced generation of cleaved-caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors. Citation Format: Jeong Yeon Jo, Dong Hoon Shin, Ji-Youn Han. Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3989.
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