Abstract MIP-048: SHORT-FORM RON KINASE AS A NOVEL THERAPEUTIC TARGET IN OVARIAN CANCER
Authors: Bieniasz Magdalena , Moxley Katherine , Wang Luyao , Welm Alana L. 
Published: June 2017

BACKGROUND: Although 70–80% of women respond to standard platinum-based chemotherapy, a majority of patients will develop recurrent platinum-resistant disease. Novel treatment approaches directed against key oncogenic drivers and/or the use of novel drug combinations to prevent/overcome platinum resistance are promising opportunities to combat this disease. sfRon is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase, the latter of which has been investigated in cancer for several years. Unlike full-length Ron, the sfRon protein lacks the extracellular ligand-binding domain, but organizes into a constitutively active transmembrane protein. Our in vitro and in vivo studies indicate that sfRon expression is associated with the acquisition of aggressive and invasive ovarian tumor phenotype. Such data carries additional importance because sfRon does not require ligand binding for activity, it may not be targetable using standard approaches such as antibody inhibitors. Instead, our data suggest that inhibition of Ron kinase activity, which would block both Ron and sfRon, might have great therapeutic benefit in ovarian tumors that express sfRon.

RESULTS: Our lab has recently made the striking and unexpected discovery that sfRon expression is necessary for development of carcinogen-driven ovarian tumors in mice. Our study involved treating wild type mice vs. mice with a specific genetic deletion of sfRon (ΔsfRon) with DMBA, a known carcinogen. The study revealed that lack of sfRon completely protected the mice from ovarian cancer. The frequency of ovarian tumors was 25% in wild-type mice vs. 0% in ΔsfRon mice (p&lt;0.0011). An increased understanding of how sfRon contributes to ovarian tumor development and progression is critical. Based on our findings supporting the role of sfRon in ovarian cancer, we aimed to investigate the expression of sfRon in primary ovarian samples. Our studies using ovarian tumors from patients revealed that sfRon becomes overexpressed in several different subtypes of ovarian cancer, with no expression in healthy ovarian tissue. Our in vitro studies revealed that introduction of sfRon into OVCAR3 cells is associated with the acquisition of aggressive and invasive tumor phenotype through the induction of EMT, increased proliferation and migration and decreased cell adhesion. The in vivo studies revealed the profound effect of sfRon expression on ovarian cancer growth and spreading to abdominal cavity. Our further studies using a large cohort of high-grade serous ovarian cancer (HG-SOC) patients demonstrated that Ron and/or sfRon are expressed in 86/126 (68%) of all cases. Statistical analysis revealed that significantly more patients in the cisplatin resistant group express high levels of Ron receptors, compared to patients in the cisplatin sensitive group, which suggest, that high levels of Ron and/or sfRon could contribute to cisplatin resistance.

CONCLUSION: Our data implicate sfRon in ovarian cancer pathogenesis, and indicate that Ron kinase inhibitors targeting both Ron and sfRon may not only suppress ovarian tumor progression, but also have potential to overcome resistance to chemotherapy. These data could have significant impact on future clinical trials for both Ron kinase inhibitors and platinum compounds, which has high potential to impact patients in the short-term.

Citation Format: Magdalena Bieniasz, Katherine Moxley, Luyao Wang, Alana L. Welm. SHORT-FORM RON KINASE AS A NOVEL THERAPEUTIC TARGET IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-048.