What Is Replicative Immortality in Cancer?

What therapies target limitless replication in cancer?

Targeted therapies for halting limitless replication in cancer revolves around interfering with the cell cycle progression in cancer cells. Several small molecule drugs targeting the cancer cell’s limitless replication have entered the clinical trial stage:

Anti Telomerase agents

Each time a cell divides, it loses a fragment of the DNA strands. In order to prevent loss of vital information, the ends of the chromosomes have extra DNA material with a repetitive sequence, known as telomeres. Telomeres have no coding function. Telomeres act like protective caps on the ends of the chromosomes to prevent DNA erosion and DNA end-to-end fusions.

With each division of cells, the telomeres get a little bit shorter in normal cells, which is one reason for aging, as well. When the telomeres get too short to prevent loss of essential DNA from the chromosome, the cell initiates apoptosis.

Except for fetal cells and stem cells, normal cells, once mature, replicate mostly during wound healing and have sufficient telomere length to last a lifetime. Cancer cells grow and divide rapidly, so loss of telomeres can lead to DNA damage and halt their progress.

Stem cells and fetal cells produce an enzyme known as telomerase to add telomere length during growth and development. Telomerase also plays a role in DNA repair. Cancer cells activate a catalytic subunit of telomerase, known as human reverse transcriptase telomerase (hTERT), and a multiprotein complex known as shelterin, which help them maintain their telomere length.

Currently, the first antitelomerase agent targeting cancer cell’s telomerase activity has entered clinical trials.

CDK inhibitors

Cyclins and cyclin-dependent kinases (CDK) are two classes of proteins that activate each of the four phases of cell cycle. CDK by themselves are inactive and cyclins bind to CDKs to activate them. Each phase of cell cycle has to be activated by a specific cyclin/CDK complex to complete the necessary process for growth, and progress past the checkpoint to the next stage.

Cyclin/CDKs inhibit the activity of an important growth inhibiting protein known as retinoblastoma, a tumor suppressing protein. Retinoblastoma protein binds to proteins known as E2 factors (E2F) and suppresses DNA transcription. 

Small molecule drugs that inhibit the different cyclin/CDK protein complexes at different cell cycle stages, are in clinical trials.

CHK inhibitors

The checkpoint mechanism is regulated by two proteins known as Checkpoint kinases (CHK1 and CHK2), which are involved in recognition of DNA damage and initiation of repair or apoptosis. Dysfunction in the checkpoint mechanism causes the CHK proteins to allow the cancer cells to progress in the cell cycle despite defects.

Small molecule inhibitors of CHKs in combination with chemotherapy or radiation are in clinical trials.

MTK inhibitors

The mitotic (M) phase in the cell cycle is a complex process where a complete copy of the whole genome is precisely segregated and pulled apart by spindles into two identical daughter cells. The different proteins that regulate this process include:

• CDK1
• Plk1 to Plk3 (pololike kinases)
• NimA-related protein kinases (Nek2)
• Auroras (A, B and C)

Auroras are mitotic kinases (MTKs) that play a critical role in the precise separation of the daughter cells. Cancer cells have an excessive presence of Auroras which cause spindle defects and imperfect segregation, leading to malignant transformation of the cell.

Pololike kinases (Plks) play a role in cell division and checkpoint regulation during mitosis. Pololike kinases have been found to be abundant in many cancers. Small molecule drugs that inhibit the activity of MTKs and Plks, and induce apoptosis, are in early stages of clinical development.

Kinesin inhibitors

Kinesin spindle proteins are responsible for the formation of spindles and proper division of the daughter cells. Blocking kinesin activity leads to cell cycle arrest and apoptosis. Kinesin inhibitors are in phase II clinical trials.

PARP inhibitors

Normal cells have pathways to repair the DNA when strand breaks or mismatches occur. Poly ADP-ribose polymerases (PARP) are a family of enzymes which open up the damaged DNA to allow access to the components that repair the damage. The PARP enzyme becomes inactive after the repair, and if repair is not possible apoptosis takes place.

In cancer cells, the repair pathways are disrupted and the cells are resistant to apoptosis. PARP inhibitors can prevent repairs of DNA breaks in cancer cells and allow the breaks to pile up, which can enhance apoptosis signals. PARP inhibitors can be used as monotherapy in certain cancers with inherited repair/apoptosis deficiency (BRCA1 or BRCA2 gene mutations), or in combination with chemotherapy or radiation.

PARP inhibitors are in early stages of clinical trials.