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Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy

Cell Death & Differentiation volume 30, pages 2491–2507 (2023)Cite this article

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Abstract

Recepteur d’origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.

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Fig. 1: Discovery of RON variants target inhibitor, WM-S1-030, as anticancer drug.
Fig. 2: Characterization of WM-S1-030, a specific inhibitor of RON variants, and analysis of its antitumor effects.
Fig. 3: Evaluation of WM-S1-030’s potential for overcoming cetuximab primary resistance, in vitro and in vivo.
Fig. 4: In vitro and In vivo effect of WM-S1-030 on RON variant-positive colon cancer.
Fig. 5: Mode of action of WM-S1-030 against colon cancer.
Fig. 6: Anticancer efficacy of WM-S1-030 in various RON variants-positive solid tumors.
Fig. 7: Immunomodulatory activity of WM-S1-030 and its potential combinatorial effect with anti-PD-1.

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Data availability

The RTK array raw data has been deposited at datadryad.org and are available from https://doi.org/10.5061/dryad.8sf7m0cvc. Additional analytical raw data are available upon reasonable request to the corresponding author.

Materials availability

All unique reagents generated in this study are available from the corresponding author with a completed Materials Transfer Agreement.

Code availability

All analysis algorithm codes follow official tutorials. Relevant information is available upon reasonable request to the corresponding author.

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Funding

This research was supported by the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (KDDF201612-12 and KDDF201812-22, Republic of Korea). The biospecimens and data used in this study were provided by the Asan Bio-Resource Center, Korea Biobank Network (2021-14(231)).

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Author notes

  1. These authors contributed equally: Joseph Kim, Dong-In Koh.

Authors and Affiliations

  1. Wellmarkerbio Co., Ltd., Seoul, Republic of Korea

    Joseph Kim, Dong-In Koh, Minki Lee, Yoon Sun Park, Seung-Woo Hong, Jae-Sik Shin, Mi So Lee, Min-Hwa Kim, Jun Hyung Lee, Joonyee Jeong, Seunggeon Bae, Jun Ki Hong, Hong-Rae Jeong, Yea Seong Ryu, Seung-Mi Kim, Mingee Choi, Hyojin Kim, Hyun Ryu, Sun-Chul Hur, Junho Park & Dong-Hoon Jin

  2. Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea

    Joseph Kim, Dong-In Koh, Minki Lee, Yoon Sun Park & Yea Seong Ryu

  3. Department of Pharmacology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Joseph Kim & Yoon Sun Park

  4. Department of Anatomy and Tumor Immunology, Inje University College of Medicine, Busan, Republic of Korea

    Dae Young Hur

  5. Department of Convergence Medicine, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea

    Dong-Hoon Jin

  6. Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Dong-Hoon Jin

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  1. Joseph Kim
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Contributions

Conceptualization: JK, DIK, and DHJ. Methodology, formal analysis and investigation: JK, SWH, DIK, JP, SCH, ML, YSP, JSS, HK, HR, SMK, MSL, MHK, JHL, JJ, SB, JKH, HRJ, YSR, MC, DYH, and DHJ. Writing-original draft: JK, SWH, DIK, and JP. Writing, review and editing: JK, DIK, JP, and DHJ. Supervision: DHJ.

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Correspondence to Dong-Hoon Jin.

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Kim, J., Koh, DI., Lee, M. et al. Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy. Cell Death Differ 30, 2491–2507 (2023). https://doi.org/10.1038/s41418-023-01235-9

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