Abstract
The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling in vitro and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development.
Highlights
High-grade serous ovarian cancer (HG-SOC) is the most common and aggressive subtype of epithelial ovarian cancer [1]
Since the focus of our research is on HG-SOC subtype that originates from fallopian tubes (15), here we analyzed and compared the full-length Ron and short-form Ron levels in human fallopian tubes and patient-derived xenografts (PDXs) derived directly from patient’s HG-SOC tumors
Previous findings demonstrated that the transcription of full-length and short-form Ron is initiated by the two independent promoters within RON (MST1R) gene, each regulated by distinct epigenetic mechanisms that leads to an independent expression of Ron isoforms in malignant tumors [8, 16,17,18]
Summary
High-grade serous ovarian cancer (HG-SOC) is the most common and aggressive subtype of epithelial ovarian cancer [1]. We explored a novel precision medicine approach in ovarian cancer by validating a multikinase inhibitor strategy targeting short-form Ron (sfRon) pathway to achieve a sustained anti-tumor response. Our previous studies showed that the sfRon pathway can be successfully targetable in cancers by Ron kinase inhibitor BMS777607 or PI3K inhibitor BKM120, respectively. These treatment regimens were unable to achieve long-lasting tumor regression after treatment cessation [9]. Targeted therapies have revolutionized the practice of oncology, still many cancers outsmart such precision-medicine efforts, which may lead to drug resistance and tumor recurrence [10, 11] This has important implications for targeting the sfRon pathway, especially since sfRon strongly www.Genes&Cancer.com induces PI3K signaling. Our data demonstrated that the AD80 therapy resulted in long-term antitumor response completely blocking metastasis development
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