Abstract A20: Short-form Ron kinase as a novel therapeutic target in ovarian cancer.

Abstract

Abstract 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. Our lab has developed a strong interest in short-form Ron (sfRon) in the context of ovarian cancer pathogenesis. 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 has more potent oncogenic activity than full-length Ron, presumably because of the constitutive kinase activity of the sfRon protein. Such data carries additional importance because sfRon does not require ligand binding for activity, appears to function in a manner distinct from full length Ron, and may not be targetable using standard approaches such as antibody inhibitors (e.g. RON8, which is now being tested in clinical trials). 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<0.0011). To our knowledge, this study is the first to show the importance of sfRon expression in development of ovarian tumors. An increased understanding of how sfRon contributes to ovarian tumor development and progression is critical. Based on these 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 studies revealed that introduction of sfRon into OVCAR-3 cells resulted in increased proliferation of tumor cells in vitro, and accelerated tumor growth in vivo as compared with parental OVCAR-3 cells. Our further studies aimed to investigate the potential clinical relevance of total Ron expression (Ron and sfRon) in a large cohort of high-grade serous ovarian cancer (HG-SOC) patients, with a particular focus on response to platinum drugs. Our data demonstrated that in the population of HG-SOC patients, Ron and/or sfRon are expressed in 86/126 (68%) of all cases, and high expression of Ron and/or sfRon was detected in 27/126 (21%) of all cases. Importantly, we also observed that significantly more patients in the cisplatin refractory/resistant group express high levels of Ron receptors (Ron and sfRon), compared to patients in the cisplatin sensitive group. 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, Alana L. Welm. Short-form Ron kinase as a novel therapeutic target in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A20.