35P - CDK7 inhibition as a promising therapeutic strategy in lung squamous cell carcinoma with SOX2 amplification

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Lung and other Thoracic Tumours
Translational Research
Presenter Jae Cheol Lee
Citation Annals of Oncology (2017) 28 (suppl_2): ii9-ii13. 10.1093/annonc/mdx089
Authors J.C. Lee1, J.Y. Hur2, J.K. Rho2, H.R. Kim2, C. Choi2
  • 1Oncology, Asan Medical Center, University of Ulsan College of Medicine, 05505 - Seoul/KR
  • 2Asan Medical Center, University of Ulsan College of Medicine, 05505 - Seoul/KR

Abstract

Background

Molecular targeted therapy has much improved the survival of lung adenocarcinoma while few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. We investigated the effects of THZ1, a potent inhibitor of cyclin-dependent kinase 7 (CDK7) which plays a key role in gene transcription, on SCC cell lines with SOX2 amplification.

Methods

SOX2-amplified SCC cell lines (H520, H1703, HCC95) and SCC cell lines without SOX2 amplification (H226, SK-MES1, H1975) were used. Along with the general drug efficacy of THZ1 and the effect of SOX2 knockout by CRISPR on cell growth, the differential gene expression following THZ1 treatment was evaluated by microarray analysis.

Results

Genetic inhibition of SOX2 by CRISPR resulted in the suppression of cell growth in SOX2-amplified SCC cell lines. The treatment of THZ1 led to the suppression of cell growth and apoptotic cell death only in SOX2-amplified SCC cell lines while the modest growth-inhibitory effect of cisplatin was not different according to the status of SOX2 amplification. The phosphorylation of carboxyl-terminal domain (CTD) of RNAPII and the expression of SOX2 and survivin were decreased by THZ1 in Western blotting. Accordingly, the expression of transcription-associated genes including SOX2 was down-regulated by THZ1 in SOX2-amplified SCC cell lines.

Conclusions

THZ1 could effectively control the proliferation and survival of SOX2-amplified SCC cells with the decrease of global transcriptional activity. It suggests that CDK7 inhibition leading to suppression of transcription may be considered as one of promising therapeutic options in lung SCC with SOX2 amplification.

Clinical trial identification

Legal entity responsible for the study

Jae Cheol Lee

Funding

Asan Medical Center

Disclosure

All authors have declared no conflicts of interest.