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Genetic Alterations in Cyclin-Dependent Kinases Highlight Potential Cancer Treatment Approach

NEW YORK – Cyclins and cyclin-dependent kinases like CDK7 and CDK12 are recurrently altered genetically in a range of cancer types, providing insight into potential treatment strategies, according to a new study. 

Cyclin-dependent kinases (CDKs) typically bind cyclins and regulate a number of downstream proteins that are key components of cell division and transcription. Because of this, CDKs have been intriguing targets for cancer therapies, and CDK4/6 inhibitors have been approved by the US Food and Drug Administration to treat women with ER-positive, HER2-negative metastatic breast cancer.

In a new study, researchers from the University of Pennsylvania now analyzed copy number gains and losses as well as other alterations affecting cyclins and CDKs in more than 10,000 tumors. As they reported in Cell Reports on Tuesday, the researchers found that cell cycle-related cyclins and CDKs were often amplified in tumors, but that copy number losses, especially affecting CDK7 and CDK12, also occurred. CDK7 influences the expression of DNA damage repair genes, and the researchers found low doses of CDK7 inhibitors could boost the sensitivity of tumor cells that otherwise were capable of homologous recombination to PARP inhibitor treatment. This could potentially expand the population for which such drugs might work.

"Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies," UPenn's Lin Zhang and his colleagues wrote in their paper.

For their analysis, the researchers determined the somatic copy number alterations, mutations, and transcript fusions affecting 21 CDK genes and 26 cyclin genes within The Cancer Genome Atlas. They identified more than two dozen CDKs and cyclins that were recurrently altered. These alterations were typically driven by somatic cell copy number alterations, whereas mutations and transcript fusions were rare.

Cell cycle-linked CDKs and cyclins were often amplified in cancers, but transcription-linked CDKs and cyclins tended to experience copy number losses.

In particular, losses affecting the closely linked genes CDK7 and CDK12 were found throughout cancer types. The researchers estimated that about 27 percent of tumors at the pan-cancer level harbored a CDK7 copy number loss. Recurrent CDK7 deletions were found among ovarian serous cystadenocarcinoma, prostate adenocarcinoma, esophageal carcinoma, cholangiocarcinoma, and triple-negative breast cancer. Recurrent CDK12 deletions, meanwhile, were present among uterine corpus endometrial carcinoma, ovarian serous cystadenocarcinoma, and lung adenocarcinoma.

Using drug screening data from the Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal projects, the researchers found that genomic loss of CDK7 or CDK12 was linked to increased sensitivity to treatment with DNA-damaging agents.

Transcriptional CDKs, the researchers noted, influence the expression of genes in DNA damage repair pathways. When dysregulated, CDK7 or CDK12 may lead to decreased expression of DNA damage repair pathway genes, leading to genomic instability and tumorigenesis. Indeed, when the researchers treated a set of cancer cell lines with the CDK7 inhibitor THZ1, the treatment repressed the expression of DNA damage repair pathway genes such as BRCA1, BRCA2, and RAD51 and affected homologous recombination (HR).

This suggested to the researchers that CDK inhibitors might make cells that are able to do HR susceptible to therapies targeting DNA damage repair pathways. When they treated HR-proficient cancer cell lines with a low dose of THZ1, the cells became sensitized to the PARP inhibitor therapy olaparib. They noted similar results in xenograft mouse tumors.

"Our genomic analysis provided an additional rationale for the clinical development of targeting transcriptional CDKs/cyclins, especially for CDK7-targeted therapy," Zhang and his colleagues wrote. "Repression of HR gene transcription and suppression of their RNA processing, subsequently leading to HR-deficiency in HR-proficient tumors, has been proposed as a strategy to treat cancer in combination with PARPis or other DNA-damaging agents."