Chordoma Foundation

CDK7/12/13 and CDK9

Cyclin-dependent kinase 7 (CDK7), Cyclin-dependent kinase 7 (CDK12), Cyclin-dependent kinase 7 (CDK13),  and Cyclin-dependent kinase 9 (CDK9) are enzymes that regulate cell transcription and are crucial regulators of cell cycle control.

Location: CDK7 chromosome 5q13.2; CDK12 chromosome 17q12; CDK13 chromosome 7p14.1; CDK9 chromosome 9q34.11

CDK7/12/13 and CDK9 are oncoproteins and targeting of these cyclin-dependent kinases with inhibitors has reduced tumor growth and suppressed cell proliferation in chordoma.

CDK7/12/13 and CDK9 in Chordoma

  • CDK7/12/13 and CDK9 are critical to normal cell growth and proliferation, and play a crucial role in regulating cell transcription. Pharmaceutical inhibitors of CDK7/12/13 and CDK9 can suppress chordoma cell proliferation and downregulated brachyury.
  • Molecular Evidence
  • Preclinical Evidence

Molecular Evidence


Protein Expression

  • CDK7 protein is well expressed in the UM-Chor1 chordoma cell line. CDK7 expression does not change upon exposure to increasing concentration of the CDK7/12/13 inhibitor THZ1.1

Preclinical Evidence


In-vitro Efficacy

  • Screening of 459 small molecules in four chordoma cell lines identified 28 anti proliferative compounds including a CDK7/12/13-targeting compound (THZ1), CDK12/13-targeting compound (THZ531) and CDK9-targeting compounds (NVP-2, AT7519, dinaciclib, alvociclib) that significantly reduced chordoma cell proliferation.1
  • CRISPR-Cas9 screening in two chordoma cell lines found that sgRNAs targeting CDK7, CDK13, and CDK9 (but not CDK12) were lethal.1
  • Chordoma cells treated with THZ1 showed reduced phosphorylation of POLR2A, increased caspase-3/7 activity, and decreased viability.1
  • THZ1, dinaciclib, and alvociclib decreased cell proliferation across a panel of chordoma cell lines.1
  • Treatment of chordoma cell lines with THZ1, dinacilib, NVP-2, and alvociclib all resulted in significantly decreased Brachyury protein expression.1
  • Treatment of chordoma cell lines with the CDK9-inhibitor TG02 resulted in decreased expression of Brachyury, reduced cell proliferation, migration, invasion, and cell cycle progression. Treatment of chordoma cell lines with TG02 and cycloheximide further reduced Brachyury protein expression.2
  • Exposure of chordoma cells to low-dose TG02 enhanced natural killer cell-mediated tumor lysis.2

In-vivo Efficacy

  • Treatment of a human xenograft model of chordoma with THZ1 inhibited tumor growth.1


1.
Sharifnia T, Wawer M, Chen T, et al. Small-molecule targeting of brachyury transcription factor addiction in chordoma. Nat Med. 2019;25(2):292-300. https://www.ncbi.nlm.nih.gov/pubmed/30664779.
2.
Seldomridge A, Sonnemann H, Jung J, et al. CBIO-01. TRANSCRIPTIONAL MODULATION OF BRACHYURY IN CHORDOMA. Neuro Oncol. 2017;19(Suppl 6):vi32-vi33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692901.

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