‘Brake’-ing the cycle

By Dr. Charles Ishak

A new class of drugs restores the brakes on cell growth
All cancers are ultimately characterized by uncontrolled cell growth. Efforts to understand how cancers cut the ‘brakes’ that control cellular proliferation have yielded a promising new class of therapeutics that demonstrate particular efficacy in breast cancers. A basic understanding of how cells control proliferation provides context to explain how these drugs function. 

Cancer cuts the brakes
Cells replicate their total genetic information, or DNA, and then split the duplicated genetic information into two separate daughter cells. Collectively, this process is referred to as the ‘cell cycle’ and is tightly controlled to ensure cells only duplicate at appropriate times throughout development. The study of a specific eye tumor found in children provided the first hints of how cancers hijack control over the cell cycle. Ground breaking work in the 1970s revealed the existence a ‘tumor suppressive’ gene that was commonly mutated in children with this type of eye tumor. This would be the first of many tumor suppressor genes that were later identified and characterized to share the common trait of preventing the initiation of tumor formation in a variety of cancers. This particular tumor suppressive gene, coined ‘retinoblastoma tumor suppressor gene’ (abbreviated as RB1) was discovered to encode a protein, called pRB, that functions as a molecular ‘brake’ to restrict a cell’s ability to initiate DNA replication and commit to another complete round of the cell cycle.

Scientists discover how cells control the brakes
Following initial identification, the role of RB1 was investigated using ‘loss of function’ studies in which scientists created mutant versions of the gene to disrupt regular function. These studies illuminated the molecular ‘levers’ responsible for applying or releasing the break on cell cycle entry. A family of proteins referred to as ‘cyclin-dependent kinases’ (CDKs) chemically modify pRB to release the cell cycle break. In contrast, proteins called cyclin-dependent kinase inhibitors (CKIs) block CDKs to maintain the cell cycle break. Scientists soon discovered that the majority of cancers exploit these ‘levers’ to release the brake rather than directly mutate the RB1 gene, as observed in childhood eye tumors. Since the majority of cancers do not mutate RB1, this suggested that break might be restored if control over the ‘levers’ could be salvaged.

Scientists develop drugs the reclaim control over the brakes
This early model of cell cycle regulation formed the basis for a rational drug design that sought to ‘re-apply’ the breaks through a drug that could inhibit CDKs. Research investigating the structure of CDKs culminated in the development of compounds that could inhibit CDKs to re-apply the pRB-mediated cell cycle break. After promising results in mouse models, clinical trials were initiated to evaluate drugs targeted against the first CDK members to modify pRB in the cell cycle, CDK4/6. CDK4/6 inhibitors from the pharmaceutical companies Pfizer, Novartis, and Eli Lilly advanced to clinical trials. Thus far, clinical trials have revealed responses in women with a particular subtype of breast cancer. In light of these observations, the US Food and Drug Administration (FDA) approved Pfizer’s compound to treat this specific subtype of breast cancer in February 2015. The success of CDK inhibitors in breast cancer underscores the value of continued support at the basic research level. It is only through the academic pursuit of basic science that opportunities for therapeutic translation are realized.

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