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

Masayuki Komatsu, Kanako Nakamura, Takashi Takeda, Fumiko Chiwaki, Kouji Banno, Daisuke Aoki, Fumitaka Takeshita, Hiroki Sasaki

Research output: Contribution to journalArticlepeer-review

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 denovoaddiction 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.

Original languageEnglish
Pages (from-to)2326-2339
Number of pages14
JournalOncogene
Volume41
Issue number16
DOIs
Publication statusPublished - 2022 Apr 15
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling'. Together they form a unique fingerprint.

Cite this