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Oncogene

Oncogene

IF: 7.3
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Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling

Published:7 March 2022 DOI: 10.1038/s41388-022-02256-3
Masayuki Komatsu, Kanako Nakamura, Takashi Takeda, Fumiko Chiwaki, Kouji Banno, Daisuke Aoki, Fumitaka Takeshita, Hiroki Sasaki

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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