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

Nature Medicine volume 24, pages 203–212 (2018)Cite this article

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Abstract

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.

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Figure 1: AXL-107-MMAE induces cytotoxicity in vitro and in vivo.
Figure 2: Elimination of distinct tumor populations by AXL-107-MMAE and MAPK pathway inhibition.
Figure 3: AXL-positive cells reside in pre-treatment melanomas and rapidly outgrow bulk AXL-negative cells following therapeutic pressure.
Figure 4: AXL-107-MMAE and MAPK inhibitors mutually potentiate cytotoxicity.
Figure 5: AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibit melanoma PDX growth.
Figure 6: Eliminating heterogeneous melanoma by targeting distinct populations with AXL-107-MMAE and MAPK pathway inhibitors.

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Acknowledgements

We thank all the members of the Peeper and Blank laboratories for their valuable input and the FACS facility and animal facility at the NKI for their support. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. We thank M. van der Ven and the intervention unit (NKI) for their help with animal experiments, M. Mertz and E. Gielen for their help with confocal microscopy, and H. Witteveen, M. Houtkamp, G. Rigter and T. Kroes for help with experiments. The research leading to these results has been funded by a grant from Genmab, by the European Research Council under the European Union′s Seventh Framework Programme (FP7/2007-2013)/ERC synergy grant agreement n° 319661 COMBATCANCER and grants NKI 2014-7241, NKI 2013-5799 and NKI 2017-10425 from the Dutch Cancer Society (KWF).

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  1. Daniel S Peeper and Paul W H I Parren: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Julia Boshuizen, Oscar Krijgsman, Aida Shahrabi, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank & Daniel S Peeper

  2. Genmab, Utrecht, The Netherlands

    Louise A Koopman, Elke Gresnigt– van den Heuvel, Nora Pencheva, Jens Thing Mortensen, Maarten L Janmaat, David Satijn, Esther C W Breij & Paul W H I Parren

  3. Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Ji-Ying Song

  4. Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    Paul W H I Parren

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Contributions

J.B., L.A.K., E.C.W.B., M.L.J., D.S., D.S.P. and P.W.H.I.P. designed the study, analyzed the data and wrote the manuscript. J.B., M.A.L., D.W.V., N.P. and E.G.-v.d.H. performed the experiments. O.K. performed the bioinformatics analyses. K.K. and D.S.P. developed the melanoma PDX-platform and engineered PDX-derived cell lines. A.S. and J.B. performed in vivo melanoma experiments. J.-Y.S. analyzed IHC from in vivo experiments. T.K. and C.U.B. gave critical input. J.T.M. directed toxicological analyses. M.G.F. and E.A.R. provided paired human melanoma samples. D.S.P. and P.W.H.I.P. supervised the study.

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Correspondence to Esther C W Breij or Daniel S Peeper.

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L.K., E.B., E.G.-v.d.H., N.P., M.J. and D.S. are full-time Genmab employees and have warrants and/or stock. P.P. is a Genmab shareholder. C.U.B. receives grants and/or research support from Novartis and BMS, and has received honoraria or consultation fees for MSD, BMS, Roche, Novartis, GSK, Pfizer and Lilly, and is a stock shareholder of Verastem.

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Boshuizen, J., Koopman, L., Krijgsman, O. et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med 24, 203–212 (2018). https://doi.org/10.1038/nm.4472

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