Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors
Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors
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DOI：
10.1038/nm.4472
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发表时间：
2018-02-01
期刊：
影响因子：
82.9
通讯作者：
Parren, Paul W. H. I.
中科院分区：
文献类型：
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作者：
Boshuizen, Julia;Koopman, Louise A.;Parren, Paul W. H. I.
肿瘤内异质性是导致治疗失败的关键因素，从而导致癌症的致命性。异质肿瘤显示部分治疗反应，允许出现耐药克隆，通常表达高水平的酪氨酸激酶AXL受体。在黑色素瘤中，axl -高的细胞对MAPK通路抑制剂有耐药性，而axl -低的细胞对这些抑制剂敏感，使差异治疗方法合理化。我们开发了一种抗体-药物偶联物，AXL-107- mmae，包含一种与微管破坏剂单甲基auristatin e连接的人AXL抗体。我们发现，AXL107-MMAE作为一种单剂，在患者来源的异种移植物中显示出有效的体内抗肿瘤活性，包括黑色素瘤、肺癌、胰腺癌和宫颈癌。通过消除异质性黑色素瘤细胞池中的不同种群，AXL-107-MMAE和MAPK途径抑制剂协同抑制肿瘤生长。此外，BRAF/MEK抑制剂通过诱导AXL转录，增强了AXL-107- mmae的疗效。这些发现为异质肿瘤中不同人群的合理联合靶向可能提高治疗效果的前提提供了概念证明，值得AXL-107-MMAE在单药或联合治疗中用于治疗初治和耐药癌症的临床验证。
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono-or combination therapy.