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

研究成果: Article査読

抄録

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.

本文言語English
ページ(範囲)2326-2339
ページ数14
ジャーナルOncogene
41
16
DOI
出版ステータスPublished - 2022 4月 15

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 癌研究

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