Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.
Athanasios R PaliourasMarta BuzzettiLei ShiIan J DonaldsonPeter MageeSudhakar SahooHui-Sun LeongMatteo FassanMatthew CarterGianpiero Di LevaMatthew G KrebsFiona BlackhallChristine M LovlyMichela GarofaloPublished in: EMBO molecular medicine (2020)
A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors.
Keyphrases
- advanced non small cell lung cancer
- drug resistant
- cell cycle arrest
- gene expression
- cell death
- induced apoptosis
- multidrug resistant
- transcription factor
- acinetobacter baumannii
- epidermal growth factor receptor
- oxidative stress
- endoplasmic reticulum stress
- heat shock
- signaling pathway
- primary care
- cell proliferation
- genome wide
- dna methylation
- combination therapy
- cystic fibrosis
- anti inflammatory