Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts.
Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts.
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DOI：
10.1158/1078-0432.ccr-14-3283
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发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
Welm AL
中科院分区：
文献类型：
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作者：
Bieniasz M;Radhakrishnan P;Faham N;De La O JP;Welm AL
最近的研究表明，短型RON(SfRon)激酶通过激活PI3K通路来驱动乳腺肿瘤的进展和转移。我们推测，预先同时抑制sfRon和PI3K可能会增强RON激酶抑制剂治疗的抗肿瘤效果，同时也可以防止对酪氨酸激酶抑制剂(TKIs)的潜在治疗耐药。我们使用患者来源的乳腺肿瘤异种移植(PDX)作为高保真的临床前模型，以确定单药或双RON/PI3K抑制的疗效。我们在激素受体阳性(ER+/PR+)伴有和不伴有PIK3CA基因突变的PDX中测试了RON激酶抑制剂ASLAN002与PI3K抑制剂NVP-BKM120联合应用的情况。携带野生型PIK3CA的乳腺PDX肿瘤作为单一药物对ASLAN002表现出强烈的反应。相反，携带突变PIK3CA的PDX肿瘤对ASLAN002表现出部分耐药性，这种耐药性可通过在治疗方案中加入NVP-BKM120来克服。我们进一步证明，在乳腺PDX肿瘤中同时抑制sfRon和PI3K和野生型PIK3CA可以在停止治疗后提供持久的肿瘤停滞，而停止任何一种单一治疗都会促进肿瘤复发。我们的工作为乳腺癌患者靶向sfRon提供了临床前的理论基础，重要的规定是，携带PIK3CA突变的肿瘤可能对RON抑制剂治疗部分耐药。我们的数据还表明，野生型PIK3CA的肿瘤使用RON和PI3K抑制剂的预先联合治疗最有效，具有最持久的反应。
Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the anti-tumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKIs). We used patient-derived breast tumor xenografts (PDXs) as high-fidelity pre-clinical models to determine the efficacy of single agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without co-administration of the PI3K inhibitor NVP-BKM120 in hormone receptor positive (ER+/PR+) breast PDXs with and without PIK3CA gene mutation. Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence. Our work provides pre-clinical rationale for targeting sfRon in breast cancer patients, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response.