Wang Luyao, Wang Lin, Cybula Magdalena, Drumond-Bock Ana Luiza, Moxley Katherine M, Bieniasz Magdalena
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Genes Cancer. 2020 Jul 22;11(3-4):106-121. doi: 10.18632/genesandcancer.205. eCollection 2020 Dec 31.
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 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 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.
sfRon激酶是卵巢癌中的一个重要治疗靶点，它促进肿瘤显著生长和疾病进展。我们推测，对sfRon通路进行多激酶抑制可能是实现持续抗肿瘤反应并同时防止治疗耐药的有效策略。我们对sfRon信号传导进行了详细剖析，并证明S6K1是sfRon表达的卵巢肿瘤多激酶靶向策略的关键组成部分。我们选择了靶向sfRon通路中包括AKT和S6K1在内的多种激酶的AD80化合物，并将其疗效与选择性靶向sfRon或PI3激酶的抑制剂进行比较。利用人卵巢异种移植瘤和临床相关的患者来源异种移植瘤（PDXs），我们证明单药AD80治疗比标准护理化疗（顺铂/紫杉醇）或BMS777607直接抑制sfRon激酶显示出更高的疗效。我们的研究结果表明，表达sfRon的卵巢肿瘤用同时靶向AKT和S6K1的多激酶抑制剂（如AD80）治疗最为有效，这会导致长期抗肿瘤反应并防止转移发展。
