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Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling

Oncogene volume 41, pages 2326–2339 (2022)Cite this article

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Abstract

Oncogenic signalling confers tumour-progression advantages; thus, its pharmacological blockade is the best strategy for cancer chemotherapy. However, drug resistance and heterogeneous dependency of tumour hamper their therapeutic potential, suggesting the necessity for a new ubiquitous modality based on evading drug resistance. Here, we proposed a de novo addiction to oncogenic signalling (Dead-On) concept, wherein specific blockade of target molecules forces cancer cells to develop dependency on an oncogenic signalling. In cervical squamous cell carcinoma cells, Aurora A/B dual blockade elicited rapid addiction to EGFR–Erk signalling, and its pharmacological/genetic inhibition synergistically enhanced anti-cancer activities in vitro, in vivo, and in a patient-derived organoid model. The signal activation was independent of EGFR genetic status, it was triggered by receptor accumulation on the plasma membrane via Rab11-mediated endocytic recycling machinery. These findings support our novel Dead-On concept which may lead to drug discovery as well as expand the adaptation of approved targeted drugs.

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Fig. 1: CvSCC cells are resistance to dual inhibition of Aurora kinase A and B.
Fig. 2: PF-03814735 induces accumulation of EGFR on plasma membrane and activates its signalling.
Fig. 3: Combinatorial treatment of Aurora kinase A/B and EGFR inhibitor synergistically induces apoptosis of SCC cells.
Fig. 4: Concurrent treatment of aurora kinase and EGFR inhibitor enhances anti-tumour activity against CvSCC.
Fig. 5: Depletion of Aurora A and B phosphorylates EGFR via promotion of endocytic recycling.

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Acknowledgements

This work was supported by Pfizer Investigator-Initiated Research (WO195177) Program and by the National Cancer Center Research and Development Fund (28-A-11, 29-A-2). We would like to thank Editage (www.editage.com) for English language editing.

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  1. These authors contributed equally: Masayuki Komatsu, Kanako Nakamura, Takashi Takeda.

Authors and Affiliations

  1. Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan

    Masayuki Komatsu, Fumiko Chiwaki, Fumitaka Takeshita & Hiroki Sasaki

  2. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan

    Kanako Nakamura, Takashi Takeda, Kouji Banno & Daisuke Aoki

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  1. Masayuki Komatsu
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Contributions

KN, TT, and MK planned the study, performed experiments, analysed the data, and wrote the manuscript; FC performed the experiments; KB and DA provided clinical samples; FT and HS conceived and planned the study, analysed the data, and wrote the manuscript. All authors have read and approved the final version of the manuscript.

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Correspondence to Masayuki Komatsu or Hiroki Sasaki.

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Komatsu, M., Nakamura, K., Takeda, T. et al. Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling. Oncogene 41, 2326–2339 (2022). https://doi.org/10.1038/s41388-022-02256-3

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