Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy.

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.

Discovery of Novel, Thienopyridine-Based Tyrosine Kinase Inhibitors Targeting Tumorigenic RON Splice Variants.

Herein, we report the identification, structural optimization, and biological efficacy of thieno[2,3-b]pyridines as potent inhibitors of splice variants of the tyrosine kinase recepteur d'origine nantais (RON). Among synthesized compounds, compound 15f exhibited excellent in vitro kinase inhibition and antiproliferative activity, as well as in vivo antineoplastic efficacy against RON splice variant-expressing tumors. Moreover, compound 15f with excellent pharmacokinetics demonstrated significant activity with greater tumor growth inhibition (74.9% at 10 mg/kg) than compounds 2 and 4 in a patient-derived xenograft model. Collectively, 15f represents a promising, novel anticancer agent targeting RON splice variants.