Abstract
We previously found the SLC3A2-NRG1 (S-N) fusion gene in a lung adenocarcinoma specimen without known driver mutations and validated this in 59 invasive mucinous adenocarcinoma (IMA) samples. Interestingly, KRAS mutation coexisted (62.5%) in 10 out of 16 NRG1 fusions. In this study, we examined the role of mutant KRAS in regulating the S-N fusion protein in KRAS mutant (H358) and wild-type (Calu-3) cells. KRAS mutation-mediated increase in MEK1/2 and ERK1/2 activity enhanced disintegrin and metalloproteinase (ADAM)17 activity, which increased the shedding of NRG1 from the S-N fusion protein. The cleavage of NRG1 also increased the phosphorylation of ERBB2-ERBB3 heterocomplex receptors and their downstream signalling pathways, including PI3K/Akt/mTOR, even under activated KRAS mutation signalling. The concurrence of S-N fusion and KRAS mutation synergistically increased cell proliferation, colony formation, tumour growth, and the cells’ resistance to EGFR kinase inhibitors more than KRAS mutation alone. Targeted inhibition of MEK1/2, and ADAM17 significantly induced apoptosis singly and when combined with each mutation singly or with chemotherapy in both the concurrent KRAS mutant and S-N fusion xenograft and lung orthotopic models. Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.
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This work was supported by grants (NCC-2010070 and 2110340) funded by the National Cancer Centre, and NRF-2021R1F1A1062721 funded by the National Research Fund.
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Conception and design: DHS and JYH. Acquisition of data: DHS, YGB, SHK, and MYC. Analysis and interpretation of data: DHS, BKC, CYH, SSK. Writing and revision of the paper: DHS.
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Shin, D.H., Kim, S.H., Choi, M. et al. Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1. Oncogene 41, 280–292 (2022). https://doi.org/10.1038/s41388-021-02097-6
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DOI: https://doi.org/10.1038/s41388-021-02097-6