CDK7 Inhibition is Effective in all the Subtypes of Breast Cancer: Determinants of Response and Synergy with EGFR Inhibition.

Cells
Martina S J McDermottEugenia V Broude

Abstract

CDK7, a transcriptional cyclin-dependent kinase, is emerging as a novel cancer target. Triple-negative breast cancers (TNBC) but not estrogen receptor-positive (ER+) breast cancers have been reported to be uniquely sensitive to the CDK7 inhibitor THZ1 due to the inhibition of a cluster of TNBC-specific genes. However, bioinformatic analysis indicates that CDK7 RNA expression is associated with negative prognosis in all the major subtypes of breast cancer. To further elucidate the effects of CDK7 inhibition in breast cancer, we profiled a panel of cell lines representing different breast cancer subtypes. THZ1 inhibited cell growth in all subtypes (TNBC, HER2+, ER+, and HER2+/ER+) with no apparent subtype selectivity. THZ1 inhibited CDK7 activity and induced G1 arrest and apoptosis in all the tested cell lines, but THZ1 sensitivity did not correlate with CDK7 inhibition or CDK7 expression levels. THZ1 sensitivity across the cell line panel did not correlate with TNBC-specific gene expression but it was found to correlate with the differential inhibition of three genes: CDKN1B, MYC and transcriptional coregulator CITED2. Response to THZ1 also correlated with basal CITED2 protein expression, a potential marker of CDK7 inhibitor sen...Continue Reading

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Citations

Jun 24, 2020·Cells·Shujing LiangAirong Qian
Apr 29, 2020·International Journal of Molecular Sciences·Yasmin M AttiaGabriel Lopez-Berestein
May 18, 2020·Current Topics in Medicinal Chemistry·Bharat GoelShreyans K Jain
Nov 14, 2020·Expert Opinion on Investigational Drugs·Hanzhi LiangHao Fang
Jun 10, 2021·Therapeutic Advances in Musculoskeletal Disease·Hangzhan MaZhenfeng Duan

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BETA
xenograft
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SPSS
CompuSyn
ImageLab
Kaplan Plotter

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