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AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma

Oncogene volume 37, pages 3275–3289 (2018)Cite this article

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Abstract

Multiple genetic mutations within melanoma not only cause lesion-specific responses to targeted therapy but also alter the molecular route of resistance to that therapy. Inactivation of PTEN occurs in up to 30% of melanomas, frequently with a concurrent activating BRAF mutation. PTEN loss regulates both acquired and intrinsic drug resistance. Here we show that AXL/AKT axis mediated-resistance to BRAF inhibitor (BRAFi) depends upon PTEN status in melanoma. Hyperactivation of both ERK and AKT pathways was associated with BRAFi resistance in melanoma with wildtype PTEN. The PTEN-impaired melanoma cells required only the ERK resistance mechanism. Moreover, we identified AXL as a key upstream effector of AKT pathway-associated resistance to BRAFi in melanoma with wildtype PTEN, but not in melanoma with impaired PTEN. Notably, we confirmed that blocking AXL by shRNA and a small molecular inhibitor could rescue the sensitivity of resistant melanoma cells with wildtype PTEN to BRAFi and inhibit their growth in vitro and in vivo. Our study has uncovered a mechanism by which PTEN status contributes to acquired resistance to BRAFi and offers a rational strategy to guide clinical testing in pre-identified subsets of patients who relapse during treatment with BRAFi. The identified protein AXL represents a promising therapeutic target for BRAF mutant melanoma patients with wildtype PTEN.

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Acknowledgements

This work was supported in part by funding from the NIH intramural research program. Thanks, are due to Dr. Miriam Anver for assistance with immunohistochemistry.

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  1. These authors contributed equally: Qiang Zuo, Jing Liu, Yanlin Yu

Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institutes, National Institutes of Health, Bethesda, MD, 20892-4264, USA

    Qiang Zuo, Liping Huang, Yifei Qin, Claire Seo, Glenn Merlino & Yanlin Yu

  2. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China

    Qiang Zuo, Jing Liu & Liping Huang

  3. Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institutes, National Institutes of Health, Bethesda, MD, 20892-4264, USA

    Teresa Hawley

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Zuo, Q., Liu, J., Huang, L. et al. AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma. Oncogene 37, 3275–3289 (2018). https://doi.org/10.1038/s41388-018-0205-4

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