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CDK7 Inhibitor Effective in Reducing Small Cell Lung Cancer in Preclinical Study

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Key Points

  • The transcription-targeting drug THZ1 inhibits cyclin-dependent kinase 7 and downregulates the expression of key transcription factors that drive small cell lung cancer.
  • Expression of super-enhancer–associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerable to THZ1 treatment.

Although small cell lung cancer is an aggressive disease with a high mortality rate, in contrast to other lung carcinomas, there has not been significant progress in the development of therapies for the disease in more than 3 decades. Now, researchers using a high-throughput cellular screen of a diverse chemical library have found that small cell lung cancer is sensitive to transcription-targeting drugs, especially THZ1, a recently identified compound that inhibits cyclin-dependent kinase 7 (CDK7). THZ1, which caused human-like small cell lung cancer tumors in mice to shrink significantly, with no apparent harmful side effects, is being developed into a drug for testing in clinical trials. The study by Christensen et al is published in Cancer Cell.

Study Methodology

To identify small molecules that suppress small cell lung cancer cell growth, the researchers performed an unbiased high-throughput screen in small cell lung cancer cell lines using a library of more than 1,000 annotated small-molecule inhibitors composed of both experimental compounds and early or advanced clinical candidates.

Study Findings

The researchers found that small cell lung cancer is sensitive to transcription-targeting drugs, particularly THZ1, which inhibits CDK7, a cell protein known to play a crucial role in gene transcription. In addition, the researchers found that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerable to THZ1 treatment. Because normal cells do not rely on super-enhancers to the same degree, they are largely unaffected by THZ1, the study found.

“We propose that downregulation of these transcription factors contributes, in part, to small cell lung cancer sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored small cell lung cancer therapy,” wrote the study authors.

“We found that small cell lung cancer cells are ‘addicted’ to transcription in a way that normal cells are not,” said Kwok-Kin Wong, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute and a co-senior author of the study, said in a statement. “They appear to depend on short-lived transcripts—briefly existing RNA copies—that aren’t as critical to normal cells. This explains why normal cells can tolerate the drug that targets the basic transcription mechanism while small cell lung cancer cells cannot.”

The key to the effectiveness of the agents derived from THZ1 will be finding the correct “therapeutic window” for patients, said Dr. Wong. Clinical trials will help determine that window.

Richard A. Young, PhD, of Massachusetts Institute of Technology, and Dr. Wong are corresponding authors for the Cancer Cell article.

The study was funded by the National Institutes of Health, the Thoracic Foundation, the Susan Spooner Foundation, the Massachusetts Institute of Technology–Dana-Farber Cancer Institute Bridge grant, and the Danish Cancer Society.

Dr. Young, Nathanael S. Gray, PhD, and James E. Bradner, MD, are founders and equity holders in Syros, which has licensed the CDK7 intellectual property from the Dana-Farber Cancer Institute. Nicholas Kwiatkowski, PhD, Tinghu Zhang, PhD, and Dr. Gray are inventors on a patent application covering THZ1.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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