Targeting cancer stemness mediated by BMI1 and MCL1 for non-small cell lung cancer treatment

Erh Hsuan Lin, Jhen Wei Hsu, Ting Fang Lee, Chiung Fang Hsu, Tsung Hsien Lin, Yi Hua Jan, Hsiang Yi Chang, Chun Ming Cheng, Hui Jan Hsu, Wei Wei Chen, Bo Hung Chen, Hsing Fang Tsai, Jung Jung Li, Chi Ying Huang, Shih Hsien Chuang, Jia Ming Chang, Michael Hsiao, Cheng Wen Wu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-associated death, with a global 5-year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug-resistance, and is a potential target for drug development. In this study, we found that in non-small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo-resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule, BI-44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI-44 provides the basis for a new therapeutic approach in NSCLC treatment.

Original languageEnglish
Pages (from-to)4305-4321
Number of pages17
JournalJournal of Cellular and Molecular Medicine
Volume26
Issue number15
DOIs
StatePublished - Aug 2022

Keywords

  • BMI1
  • MCL1
  • NSCLC
  • cancer stemness
  • small-molecule therapy

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