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 AXL-107-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.

中文翻译：

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与AXL抗体-药物偶联物和BRAF / MEK抑制剂协同靶向黑色素瘤异质性。

肿瘤内异质性是导致治疗失败并因此导致癌症致死性的关键因素。异质性肿瘤显示出部分治疗反应，允许出现耐药性克隆，这些克隆通常表达高水平的受体酪氨酸激酶AXL。在黑色素瘤中，高AXL的细胞对MAPK途径抑制剂具有抗性，而低AXL的细胞对这些抑制剂敏感，从而合理化了差异性治疗方法。我们开发了一种抗体-药物偶联物AXL-107-MMAE，其中包含与微管破坏剂单甲基澳瑞他汀E连接的人AXL抗体。我们发现，AXL-107-MMAE作为一种单一药物，在体内具有强大的抗患者来源的异种移植物中的肿瘤活性，包括黑色素瘤，肺癌，胰腺癌和宫颈癌。通过消除异质黑素瘤细胞库中的不同种群，AXL-107-MMAE和MAPK途径抑制剂可协同抑制肿瘤的生长。此外，通过诱导AXL转录，BRAF / MEK抑制剂增强了AXL-107-MMAE的功效。这些发现为以下前提提供了概念验证：合理地组合靶向异质性肿瘤中不同人群的靶向治疗可以改善治疗效果，并值得AXL-107-MMAE在单一或联合治疗的初治和耐药性癌症中进行临床验证。