Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America.
Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America.
PLoS One. 2019 Aug 1;14(8):e0220101. doi: 10.1371/journal.pone.0220101. eCollection 2019.
Tyrosine kinase inhibitors (TKIs) that primarily target angiogenesis are approved to treat several cancers in the metastatic setting; however, resistance is common. Sequential treatment or 'switching' from one TKI to another following failure can be effective, but predicting which drugs will have cross-over sensitivity remains a challenge. Here we examined sitravatinib (MGCD516), a spectrum-selective TKI able to block MET, TAM (TYRO3, AXL, MerTK) and multiple receptor families (including PDGFRs, VEGFRs, and Ephs). Transcriptomic analysis of several mouse and human cell lines revealed diverse molecular changes after resistance to two TKIs (sunitinib and axitinib) with multiple sitravatinib targets found to be upregulated. Sitravatinib treatment in vitro resulted in enhanced anti-proliferative effects in resistant cells and was improved compared to TKIs with similar target profiles. In vivo, primary tumor growth inhibition after sitravatinib treatment in mice was enhanced in resistant tumors and metastasis suppression improved when tumors were surgically removed. Together, these results suggest that the diverse and often inconsistent compensatory signaling mechanisms found to contribute to TKI resistance may paradoxically improve the tumor-inhibiting effects of broad-spectrum TKIs such as sitravatinib that are able to block multiple signaling pathways. Sitravatinib in the second-line setting following antiangiogenic TKI treatment may have enhanced inhibitory effects in local and disseminated disease, and improve outcomes in patients with refractory disease.
酪氨酸激酶抑制剂（TKIs）主要针对血管生成，已被批准用于治疗转移性环境中的几种癌症；然而，耐药性很常见。在失败后，连续治疗或“切换”从一种 TKI 到另一种 TKI 可能是有效的，但预测哪些药物具有交叉敏感性仍然是一个挑战。在这里，我们研究了 sitravatinib（MGCD516），一种谱选择性 TKI，能够阻断 MET、TAM（TYRO3、AXL、MerTK）和多个受体家族（包括 PDGFRs、VEGFRs 和 Ephs）。几种小鼠和人类细胞系的转录组分析显示，对两种 TKI（舒尼替尼和阿昔替尼）的耐药性后存在多种分子变化，发现多个 sitravatinib 靶标上调。在体外，在耐药细胞中，sitravatinib 治疗导致抗增殖作用增强，并且与具有相似靶谱的 TKI 相比得到改善。在体内，在用 sitravatinib 治疗后，耐药肿瘤中的原发性肿瘤生长抑制增强，并且当肿瘤通过手术切除时，转移抑制得到改善。总之，这些结果表明，导致 TKI 耐药的多种且常常不一致的代偿性信号传导机制可能会反直觉地增强广谱 TKI（如 sitravatinib）的肿瘤抑制作用，这些 TKI 能够阻断多种信号通路。在抗血管生成 TKI 治疗后，二线治疗中的 sitravatinib 可能在局部和播散性疾病中具有增强的抑制作用，并改善难治性疾病患者的结局。
