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

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

  • Oncogene. 2023 Aug 17. doi: 10.1038/s41388-023-02810-7.
Kento Okamoto 1,  Toshinori Ando 2,  Hiroki Izumi 3,  Susumu S Kobayashi 4 5,  Tomoaki Shintani 6,  J Silvio Gutkind 7 8,  Souichi Yanamoto 1,  Mutsumi Miyauchi 9,  Mikihito Kajiya 6
Affiliations

Affiliations

  • 1 Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • 2 Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan. toando19@hiroshima-u.ac.jp.
  • 3 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 4 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
  • 5 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 6 Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan.
  • 7 Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • 8 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
  • 9 Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
PMID: 37591955 DOI: 10.1038/s41388-023-02810-7
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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