RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets

Table 1 Tyrosine kinase inhibitors and antibody drug conjugates specific to c-MET and RON

Therapeutic agents	Manufacturer	Target	In vitro effects	Effects in animal tumor models	Clinical trial information	Status	Ref.
TKIs
Foretinib	GlaxoSmithKline	MET, RON, VEGFR2, and PDGFRβ	Inhibits MET and RON signaling and cell growth in various cancer cell lines	Attenuates MET- and RON-mediated tumor growth in mouse tumor xenograft models	Single agent and combination with erlotinib or lapatinib for various types of advanced cancers in Phase II/III clinical trials	Phase I/II/III	Eder et al[82]
MGCD265	MethylGene	MET, RON, VEGFR1, VEGFR2, VEGFR3, and TIE2	Inhibits MET and RON signaling and cell growth in cancer cell lines	Attenuates MET- and RON-mediated tumor growth in mouse tumor xenograft models	Single agent and combination with erlotinib or docetaxel for NSCLC in Phase II trials	Phase I/II	Belalcazar et al[83]
BMS-777607	Bristol-Myers Squibb	RON and MET	Inhibits MET and RON signaling, cell growth, and invasion in cancer cell lines	Inhibits MET- and RON-mediated tumor growth in mouse tumor xenograft models	Multiple ascending doses for metastatic cancers in Phase I trials	Phase I	Sharma et al[84]
MK-2461	Merck	MET, RON, FLT1, FLT3, FGFR1, FGFR2, and FGFR3	Inhibits MET and RON signaling, cell growth, and migration in cancer cell lines	Inhibits MET- and RON-mediated tumor growth in mouse tumor xenograft models	Antitumor efficacy is under evaluation in Phase II trials	Phase I/II	Pan et al[85]
MK-8033	Merck	MET and RON	Inhibits MET and RON signaling, cell growth, and migration in cancer cell lines	Causes tumor regression in mouse tumor xenograft models	Safety, tolerability, dose, clinical activity and pharmaco-dynamics are under evaluation in Phase I trials	Phase I	Northrup et al[86]
PHA665752	Pfizer	MET and RON	NA	NA	NA	Preclinical	Comoglio et al[87]
INC280	Novartis	MET	NA	NA	NA	Phase I/II	Qin et al[88]
Tivantinib	ArQule	MET	NA	NA	NA	Phase II/III	Rimassa et al[89]
Antibody drug conjugates
Zt/g4-doxorubicin-immuoliposome	TTUHSC	RON	Moderately activates RON signaling and strongly induces RON endocytosis	No effect as naked antibody but completely inhibits tumors used as ADCs	NA	Preclinical	Guin et al[90]
Zt/g4-maytansinoid conjugate	TTUHSC	RON	Moderately activates RON signaling and strongly induces RON endocytosis	No effect as naked antibody but completely inhibits tumors used as ADCs	NA	Preclinical	Feng et al[91]
Zt/g4-MMAE	TTUHSC	RON	Moderately activates RON signaling and strongly induces RON endocytosis	No effect as naked antibody but completely inhibits tumors used as ADCs	NA	Preclinical	Yao et al[92]
H5B14-MMAE	TTUHSC	RON	NA	NA	NA	Preclinical	Yao et al[59]
SHR-A1403	HengRui	MET	Highly potent: 0.02 to 1.5 nmol/L for cell proliferation	Xenografts and PDXs, MET over-expressed and amplified	NA	Phase I	Yang et al[93]

TKIs: Tyrosine kinase inhibitors; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; NSCLC: Non-small cell lung cancer; FGFR: Fibroblast growth factor receptor; ADC: Antibody-drug conjugate; MMAE: Monomethyl auristatin E; NA: Not available; PDX: Patient-derived xenografts.