Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Nat Med. 2018 Feb;24(2):203-212. doi: 10.1038/nm.4472. Epub 2018 Jan 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / immunology
  • Genetic Heterogeneity / drug effects
  • Humans
  • Immunoconjugates / immunology
  • Immunoconjugates / pharmacology*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / immunology
  • Melanoma / pathology
  • Mice
  • Oligopeptides / chemistry
  • Oligopeptides / immunology
  • Oligopeptides / pharmacology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / immunology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins / pharmacology
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / immunology
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Receptor Protein-Tyrosine Kinases / pharmacology
  • Xenograft Model Antitumor Assays


  • Immunoconjugates
  • Oligopeptides
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • monomethyl auristatin E
  • Axl Receptor Tyrosine Kinase