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AXL activates YAP through the EGFR–LATS1/2 axis and confers resistance to EGFR-targeted drugs in head and neck squamous cell carcinoma

Oncogene volume 42, pages 2869–2877 (2023)Cite this article

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Abstract

The Hippo signaling pathway and its downstream effector YAP play a central role in cell proliferation. Dysregulation of the Hippo pathway triggers YAP hyperactivation, thereby inducing head and neck squamous cell carcinoma (HNSCC). Recently, we reported that EGFR promotes tyrosine phosphorylation of MOB1 and subsequent LATS1/2 inactivation, which are core components of the Hippo pathway, resulting in YAP activation. However, EGFR-targeted monotherapy has shown a low response rate in HNSCC patients. Given that YAP is activated in patient samples refractory to EGFR-targeted therapy, EGFR inhibitors may temporarily inactivate YAP, but intrinsic hyperactivation or acquired reactivation of YAP may confer resistance to EGFR inhibitors in HNSCC cells. The mechanism by which YAP is activated in HNSCC resistant to EGFR inhibitors remains unclear. Comprehensive transcriptional analysis revealed that AXL activates YAP through a novel mechanism: AXL heterodimerizes with EGFR, thereby activating YAP via the EGFR–LATS1/2 axis. The combination of AXL and EGFR inhibitors synergistically inactivates YAP and suppresses the viability of HNSCC and lung adenocarcinoma cells. In turn, LATS1/2 knockout and YAP hyperactivation confer resistance to the synergistic effects of these inhibitors. Our findings suggest that co-targeting both AXL and EGFR represent a promising therapeutic approach in patients with EGFR-altered cancers.

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Fig. 1: AXL expression is positively correlated with YAP activation and EGFR expression in HNSCC.
Fig. 2: AXL inhibitor inactivates YAP and is refractory to YAP-activated cancer cells.
Fig. 3: AXL heterodimerization with EGFR activates YAP.
Fig. 4: LATS1/2 KO rescues the synergistic effect of EGFR and AXL inhibitors.

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Data availability

CCLE data set is available online (https://portals.broadinstitute.org/ccle). TCGA data is available from c-bioportal (https://www.cbioportal.org/). The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by JST SPRING, Grant Number JPMJSP2132, JP20K18477, “Nozomi h foundation” from the Hiroshima University Foundation, and the JST HIRAKU-Global program.

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Authors and Affiliations

  1. Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Kento Okamoto & Souichi Yanamoto

  2. Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan

    Toshinori Ando, Tomoaki Shintani & Mikihito Kajiya

  3. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Hiroki Izumi

  4. Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan

    Susumu S. Kobayashi

  5. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Susumu S. Kobayashi

  6. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    J. Silvio Gutkind

  7. Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA

    J. Silvio Gutkind

  8. Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Mutsumi Miyauchi

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Contributions

KO and TA initiated the study; KO, TA, MM, SY, JSG and MK designed the study and experiments; KO and TA performed genomic analysis; KO and TA performed in vitro experiments; KO, TA, MM, SY, JSG and MK prepared the manuscript; TS, DI, SK and JSG provided advice; and TA supervised the project. All authors have discussed the results and reviewed the manuscript.

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Correspondence to Toshinori Ando.

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JSG is a member of the advisory board of Domain Therapeutics, io9, and Pangea, and founder of Kadima Pharmaceuticals. The remaining authors declare no conflicts of interest.

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Okamoto, K., Ando, T., Izumi, H. et al. AXL activates YAP through the EGFR–LATS1/2 axis and confers resistance to EGFR-targeted drugs in head and neck squamous cell carcinoma. Oncogene 42, 2869–2877 (2023). https://doi.org/10.1038/s41388-023-02810-7

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