Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up-regulation

Xiaoliang Zhao, In Kyu Kim, Bhaskar Kallakury, Joeffrey J. Chahine, Eiji Iwama, Mariaelena Pierobon, Emanuel Petricoin, Justine N. McCutcheon, Yu Wen Zhang, Shigeki Umemura, Vincent Chen, Changli Wang, Giuseppe Giaccone

研究成果: Contribution to journalArticle査読

3 被引用数 (Scopus)

抄録

Platinum-based chemotherapy has been the cornerstone treatment for small cell lung cancer (SCLC) for decades, but no major progress has been made in the past 20 years with regard to overcoming chemoresistance. As the cell cycle checkpoint kinase 1 (Chk1) plays a key role in DNA damage response to chemotherapeutic drugs, we explored the mechanisms of acquired drug resistance to the Chk1 inhibitor prexasertib in SCLC. We established prexasertib resistance in two SCLC cell lines and found that DNA copy number, messengerRNA (mRNA) and protein levels of the cell cycle regulator Wee1 significantly correlate with the level of acquired resistance. Wee1 small interfering RNA (siRNA) or Wee1 inhibitor reversed prexasertib resistance, whereas Wee1 transfection induced prexasertib resistance in parental cells. Reverse phase protein microarray identified up-regulated proteins in the resistant cell lines that are involved in apoptosis, cell proliferation and cell cycle. Down-regulation of CDK1 and CDC25C kinases promoted acquired resistance in parental cells, whereas down-regulation of p38MAPK reversed the resistance. High Wee1 expression was significantly correlated with better prognosis of resected SCLC patients. Our results indicate that Wee1 overexpression plays an important role in acquired resistance to Chk1 inhibition. We also show that bypass activation of the p38MAPK signaling pathway may contribute to acquired resistance to Chk1 inhibition. The combination of Chk1 and Wee1 inhibitors may provide a new therapeutic strategy for the treatment of SCLC.

本文言語英語
ページ(範囲)1130-1145
ページ数16
ジャーナルMolecular Oncology
15
4
DOI
出版ステータス出版済み - 4 2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 遺伝学
  • 腫瘍学
  • 癌研究

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