Movers and SHAKERS
The Importance of CDKs (Cyclin-dependent kinases)
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Cell proliferation is a tightly regulated process by the cell cycle machinery in normal tissues, while dysregulated cellular proliferation and aberrant proliferation is a hallmark of cancer. Cyclin-dependent kinases (CDKs) are critical regulatory enzymes that drive cell cycle transitions, control cell division and proliferation. Many of the key concepts of CDK biology were discovered over 20 years ago through the study of yeast. In 2001, Doctor Leland H. Hartwell, R. Timothy Hunt and Paul M. Nurse were awarded the Nobel Prize for their discoveries of “key regulators of the cell cycle”.
There are currently >20 members of the CDK family. The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6) are regulators of cell cycle and signal through cell cycle pathway involving p16, an endogenous suppressor of CDK4/6, cyclin D1, the regulatory subunit of CDK4/6, and retinoblastoma (Rb) protein, a tumor suppressor. Controlled phosphorylation and deactivation of the Rb protein by the CDK4/6 complex is crucial for the normal cell cycle progression. Unhindered activity of CDK4/6 pathway can result in alterations of cyclin-dependent kinases stimulating cell cycle pathway and cell proliferation in cancer cells. Selective CDK4/6 inhibitors “turn off” these kinases and dephosphorylation of Rb, resulting in a block of cell-cycle progression preventing the proliferation of cancer cells.
Figure 1. Immune Mechanism in Response to CDK4/6 Inhibitors
Source: AACR 2018
Momentum is building after recent success.
The CDK4 and CDK6 has markedly changed the perception of CDKs as therapeutic targets in cancer. There are currently three selective CDK4/6 inhibitors approved by the U.S. Food and Drug Administration (FDA) for treating hormone receptor–positive breast cancer in combination with hormonal therapy (HR+) HER2 negative (HER2–) metastatic breast cancer (MBC): Pfizer’s palbociclib (Ibrance), Novartis’s ribociclib (Kisqali) and Eli Lilly’s abemaciclib (Verzenio)
All three agents in combination with aromatase inhibitors showed equally effective clinical benefit in overall response rate (ORR), progression free survival (PFS), and a slightly different but near-identical spectrum of adverse events. Ibrance was the first to the market, winning FDA clearance in 2015. In 2018, Ibrance sales reached $4,118 million (90% of the market), while sales of Kisqali and Verzenio were $235 million and $255 million, respectively. The clinical and commercial success of CDK4/6 inhibitors in metastatic breast cancer have led to the enrichment of the product pipeline with the addition of many other CDK and CDK4/6 inhibitors including:
- Lerociclib in non-small cell lung cancer (NSCLC) and breast cancer at Phase 1/2 stage
- SEL24 in acute myelogenous leukemia (AML) at Phase 1/2 stage
- CYC065 in chronic lymphocytic leukemia (CLL) at Phase 1 stage
- SY-1365 in solid tumors at Phase 1 stage
- ON 123300 in CDK4/6 overactive tumors at pre-IND stage
Past results are discouraging.
Despite significant efforts to translate scientific knowledge into clinical development of CDK inhibitors, clinical results have been disappointing in the past. Flavopiridol, a first-generation CDK inhibitor, was investigated in more than 60 clinical trials between 1998 and 2014. Flavopiridol did not meet the initial high expectations as it showed minimal clinical benefit in patients. Despite evidence of clinical activity in haematological malignancies, such as chronic lymphocytic leukaemia (CLL, 40% response rate), Phase 3 clinical development was halted in 2012 based on lack of durable response and high disease burden in patients.
The second-generation CDK inhibitors, e.g. AZD5438, have also been extensively studied in the clinic. The efforts to achieve increasing potency and selectivity did not meet expectations. As such, development of second generation CDK inhibitors was terminated. Experts believe the failure of these drugs in the clinic could be due to the following:
- Lack of full understanding of the mechanism of action
- Poor selective targeting of CDK isoforms
- Inappropriate patient selection
- Lack of differentiation between healthy and cancerous tissues
Overall positive outlook for CDK inhibitors.
Fundamentally, the cell cycle process and cyclin-dependent kinases (CDKs) are critical regulators of cell replication, migration of survival. Deeper understanding of the biology of CDKs has been instrumental to the development of more potent CDK inhibitors, particularly in regard to determining biomarker and combination strategies. The key points to success include:
- specificity of the inhibitors in vivo and in vitro
- selection of patients
- selection of effective combinational strategies
Given the critical roles that CDKs play in multiple aspects of cell biology, CDKs inhibitors as a drug class is perceived as significant cancer therapeutics. The positive clinical data and commercial success of dual CDK4 and CDK6 inhibitors suggest that these candidate medicines could potentially be efficacious in many cancer indications.
Asghar et al. “The history and future of targeting cyclin-dependent kinases in cancer therapy” Nat Rev Drug Discov. 2015 February; 14(2): 130–146
Ameratunga et al. “To cycle or fight - CDK 4/6 inhibitors at the crossroads of anti-cancer immunity” Clinical Cancer Research 2018