MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages

Babicky, Michele; Harper, Megan M.; Chakedis, Jeffery; Cazes, Alex; Mose, Evangeline; Jaquish, Dawn; French, Randall; Childers, Betzaira G.; Alakus, Hakan; Schmid, Michael C.; Foubert, Phillippe; Miyamoto, Jaclyn; Holman, Patrick; Walterscheid, Zakkary J; Tang, Chih‐Min; Varki, Nissi; Sicklick, Jason K.; Messer, Karen; Varner, Judith A.; Waltz, Susan E.; Lowy, Andrew M.

doi:10.1038/s41388-019-0811-9

Cited by 29 publications

(28 citation statements)

References 32 publications

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“…In a recent study by Babicky ML et al, they found that RON expression can accelerate pancreatic carcinogenesis and loss of functional RON slows progression to pancreatic cancer. They also found RON knockdown significantly inhibits tumor growth in vivo (20). In the future, we suggest that the combined detection of RON and MET in tumor tissue has better clinical value for the pathological diagnosis and prognosis evaluation in patients with pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer

Hong

et al. 2019

Front. Oncol.

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RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo. There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro. They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

“…RON is more meaningful as a new target of future pancreatic cancer treatment. This may be because RON can mediate oncogenic phenotypes and addiction to KRAS signaling (20). Some researchers have found that “KRAS addiction” is associated with EMT (epithelial to mesenchymal transition) and tumor cell survival (44).…”

Section: Discussionmentioning

confidence: 99%

Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer

Hong

et al. 2019

Front. Oncol.

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“…Previous studies also have shown that RON activation reduced the polarization of inflammatory M1 macrophages and induced the differentiation of immunosuppressive M2 macrophages. M2 macrophages promote PD-L1 expression through autocrine VEGF signaling(49,50). In our study, we demonstrate that high expression of both RON and PD-L1 (TIMC) is associated with poor overall survival in patients with CRC.…”

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confidence: 51%

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

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“…1,2 In the case of pancreatic cancer, aberrant RON expression and signaling play a critical role in regulating cancer cells growth, invasiveness, and chemoresistance. 7,23,24,[26][27][28][29] Studies using a mouse model of K-RAS-driven pancreatic cancer further demonstrate that RON overexpression not only increases acinar-ductal metaplasia formation but also accelerates the progression of pancreatic intraepithelial neoplasia towards adenocarcinomas. 27 In breast cancer, RON activates several signaling pathways critical for proliferation, invasiveness, and stemn ess.…”

Section: Aberrant Ron Expression and Signaling In Cancer Pathogenesismentioning

confidence: 99%

Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

et al. 2020

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The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

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MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages

Cited by 29 publications

References 32 publications

Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer

Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

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