Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN–mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways. Mol Cancer Ther; 16(11); 2340–50. ©2017 AACR .

中文翻译：

---

抑制肿瘤生长和转移的双功能MAPK / PI3K拮抗剂。

对靶向疗法的反应经常是短暂的，患者复发时会出现耐药性肿瘤。对于致癌性MEK和BRAF抑制，通常通过激活PI3K / AKT / mTOR信号和调节免疫检查点来产生耐药性，从而为伴随治疗提供了强大的分子靶标。在这里，我们评估了同时靶向MAPK和PI3K信号通路的双功能激酶抑制剂（ST-162）的功效。ST-162的治疗可导致突变的KRAS或BRAF上瘾的结直肠癌和黑色素瘤异种移植模型退化，以及BRAF / PTEN突变型黑色素瘤停滞。将ST-162与免疫检查点阻滞剂组合使用，可在同基因KRAS突变型结直肠癌模型中进一步提高疗效。新生的转录组分析揭示了由ST-162调控的与黑色素瘤转移相关的独特基因集。随后的小鼠研究表明，ST-162是黑色素瘤向肝脏转移的有效抑制剂。这些发现突出了具有多激酶活性的单个分子在控制肿瘤，克服耐药性和通过调节相互连接的细胞信号传导途径预防转移方面的巨大潜力。分子癌疗法；16（11）; 2340–50。©2017 AACR。