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Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1

Oncogene volume 41, pages 280–292 (2022)Cite this article

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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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Fig. 1: Coactivation of SLC3A2-NRG1 (S-N) fusion and KRAS mutation increases the proliferation of KRAS mutant cell lines in lung cancer.
Fig. 2: Simultaneous activation of S-N fusion and KRAS mutation results in higher afatinib resistance than the activation of each gene individually.
Fig. 3: S-N fusion and KRAS mutation synergistically augment cancer cell proliferation.
Fig. 4: Induction of ADAM17 by KRAS mutation promotes the cleavage of S-N fusion protein.
Fig. 5: GM6001-mediated inhibition of ADAM17 reduces proliferation of cells harbouring S-N fusion and KRAS mutation.
Fig. 6: Inhibitors of ADAM17 and MEK exhibit anti-tumour effect in a xenograft mouse model of S-N fusion and KRASG12C.
Fig. 7: GM6001 and AZD6244 decreases S-N fusion and KRASG12C-induced lung tumorigenesis.

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Acknowledgements

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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  1. These authors contributed equally: Dong Hoon Shin, Ji-Youn Han.

Authors and Affiliations

  1. Research Institute, Goyang-s, Republic of Korea

    Dong Hoon Shin, Sun Ha Kim, Minyoung Choi, Young-Ki Bae, Chungyong Han, Beom K. Choi, Sang Soo Kim & Ji-Youn Han

  2. Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea

    Dong Hoon Shin & Sun Ha Kim

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Contributions

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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Correspondence to Dong Hoon Shin or Ji-Youn Han.

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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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