ONCAlert | 2017 San Antonio Breast Cancer Symposium

Clinical Development of Cyclin-Dependent Kinase Inhibitors in Lung Cancer

Ajay Dhakal, MBBS; Jiang Yio, MD, MBA; and Grace K. Dy, MD
Published Online: Mar 01,2017

Ajay Dhakal, MBBS

Abstract


A dysregulated cell cycle can lead to cancer. The retinoblastoma (RB1) gene is a tumor suppressor gene and its corresponding protein Rb has an integral role in cell-cycle regulation. Dephosphorylated Rb halts the cycle while phosphorylated Rb restarts it. Cyclin-dependent kinase (CDK) 4 and 6 are responsible for phosphorylating Rb, D-type cyclins, which are expressed in response to stimulatory mitogens, are CDK activators while p16INK4a encoded by the CDKN2A gene is an innate CDK inhibitor. CDKs have a vital role in unleashing cell cycle arrest and are targeted by a class of antitumor drugs called CDK inhibitors.

 

Inactivation of Rb pathway is seen in more than 70% of non–small cell lung cancer (NSCLC). The most common event for inactivation is the loss of CDK2NA gene. Moreover, this inactivation occurs frequently in patients with mutant KRAS lung adenocarcinomas. Early-phase studies have shown that CDK inhibition can induce immediate senescence of NSCLC with KRAS mutation. In addition, CDK4 and cyclin D1 amplifications have also been associated with lung cancer, specifically squamous cell lung cancer. Thus, there has been a significant interest in investigating the role of CDK inhibitors in lung cancer. Various broad spectrum nonselective first generation CDK inhibitors encountered obstacles in clinical development due to poor pharmacokinetic profiles and toxicities. This review article will focus on the therapeutic relevance of newer generation selective CDK inhibitors which have recently progressed the furthest in clinical development in lung cancer.
 

 

Jiang Yio, MD, MBA



Introduction

 

Cell-cycle dysregulation is one of the hallmarks of cancer.1 Various genes and their corresponding proteins, interact with each other, external stresses, hormones, and cytokines to regulate the cell cycle. Alteration in the regulatory pathways may lead to the dysregulation of cell cycle and tumorigenesis. Cyclin-dependent kinases (CDKs) are serine/threo- nine kinases that by definition require activation by cyclins or cyclin-related proteins and have been implicated in unleashing the cell-cycle arrest, and thus, they have been targeted by a class of antitumor drugs called CDK inhibitors. Excluding the related CDK1 (also known as CDC2)-like kinases, there are currently 20 members of the CDK family, several of which function in non–cell cycle processes such as transcription. Various broad-spectrum, nonselective first-generation CDK inhibitors, such as avopiridol, encountered obstacles in clinical development due to a poor pharmacokinetic profile and/or toxicities. We will focus our discussion on the therapeutic relevance of newer generation selective CDK inhibitors that have recently progressed the furthest in clinical development in lung cancer.
 

Grace K. Dy, MD


Cell-Cycle Dysregulation in Cancer

 

The retinoblastoma (RB1) gene is a tumor-suppressor gene that encodes for the retinoblastoma protein, pRb. The Rb protein undergoes intermittent phosphorylation as the cell traverses the cell cycle. A dephosphorylated Rb protein acts as a brake in the cell-cycle progression. Rb is dephosphorylated (activated) as the cell exits mitosis, is hyperphosphorylated (inactivated) toward the end of G1 phase, and remains hyperphosphorylated until the cell goes to mitosis phase.2 CDKs regulate both the cell cycle and transcription. CDKs 1, 2, 4, and 6 are required for the correct timing and order of the events of the cell-division cycle. CDK7 is a component of the CDK-activating complex that contributes to the assembly of CDK1/cyclin B. In addition, CDKs 7, 8, and 9 function as transcriptional CDKs.3 CDK4 and CDK6 phosphorylate the Rb protein, thus releasing the cell-cycle arrest during the G1 phase. CDK4 and CDK6 are activated by D-type cyclins, which are expressed in response to various extracellular signals such as stimulatory mitogens, inhibitory cytokines, cell–cell contact, and other spatial cues.2 These CDKs are inhibited by phosphorylation, ubiquitination, and binding of the endogenous cellular inhibitor p16INK4a (Figure 1). p16INK4a is encoded by CDKN2A (also known as ARF or INK4a) and its expression is induced by variety of hyperproliferative stress signals.4 Thus, competition between stress-activated p16INK4a and mitogen-activated D-type cyclins to bind with CDKs determines whether the cell stays in G1 arrest or proceeds to S phase.2 Regulation of CDKs by p16INK4a is often disrupted in cancer cells, causing increased activity of CDKs. Additionally, p16INK4a expression suppresses tumorigenic effects in cancer cell lines.5 Many studies identify the CDKN2A gene as a frequent target of inactivating mutations and deletions in many human cancers, and show that the loss-of-function alterations in genes encoding p16INK4a and pRb are mutually exclusive events in tumor cells.6 There are enough preclinical data suggesting the role of CDKs in tumorigenesis. Hence, CDKs have been investigated as antitumor drug targets. CDK expression and assembly with D-type cyclins depend on the activation of the RAS-dependent kinase cascade involving the sequential activation of RAF1, MEK1, MEK2, and ERKs. Similarly, a separate RAS signaling pathway involving PI3k and AKT also prevents phosphorylation of D-type cyclins. Cancer-specific mutations affecting receptor tyrosine kinases (RTKs), RAS, RAF, PI3K, or PTEN can enhance D-type cyclin-dependent CDK4/6 activities, thus promoting oncogenesis. Conversely, inhibitors of these intracellular signaling cascades such as antiproliferative cytokines and antagonists of hormones and interleukins can decrease the activity of CDK4 and CDK6, inducing cell-cycle arrest.8


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Clinical Development of Cyclin-Dependent Kinase Inhibitors in Lung Cancer
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