Within our bodies, genes provide the instructions for building and maintaining cellular functions. Occasionally, these genetic instructions can be altered. One such alteration is gene amplification, a process where a cell creates multiple copies of a specific gene. This results in an excess of the protein that the gene is responsible for creating. While this can happen with many genes, the amplification of the CCNE1 gene is a notable event in the development of certain cancers, disrupting the orderly process of cell life and death and contributing to tumor growth.
The Role of the CCNE1 Gene in Cell Division
The CCNE1 gene holds the blueprint for a protein called Cyclin E1. This protein is a component of the cell’s internal clock, known as the cell cycle, which governs a cell’s growth and division. Cyclin E1’s primary responsibility is to regulate a checkpoint, the transition from the G1 phase to the S phase. During the G1 phase, the cell grows in size, and in the S phase, it duplicates its DNA in preparation for dividing into two new cells.
To perform its function, Cyclin E1 partners with and activates another protein, cyclin-dependent kinase 2 (CDK2). This Cyclin E1-CDK2 complex acts like a gatekeeper, and its activation is the signal that allows the cell to move past the G1 checkpoint and begin the process of DNA synthesis. The levels of Cyclin E1 protein are normally tightly controlled; they rise as the cell approaches the S phase and are quickly degraded once DNA replication is underway to ensure division happens only at the appropriate time.
How CCNE1 Amplification Drives Cancer Growth
When the CCNE1 gene is amplified, it leads to the overproduction of the Cyclin E1 protein. This excess of Cyclin E1 overwhelms the cell’s normal regulatory systems. The constant presence of high levels of Cyclin E1 forces the cell to prematurely enter the S phase, initiating DNA replication before it is properly prepared. This effectively jams the accelerator on the cell cycle, leading to uncontrolled and rapid cell division.
This rushed and unregulated division process has further consequences that contribute to a cancer’s aggressiveness. The hurried transition into DNA synthesis creates what is known as replication stress, where the machinery that copies DNA is more prone to making mistakes. This leads to an accumulation of mutations and chromosomal abnormalities, a condition called genomic instability. This instability can cause further mutations in other genes that control cell survival and proliferation, making the cancer cells more adaptable and aggressive.
Cancers Associated with CCNE1 Amplification
CCNE1 amplification is a known driver in several specific types of cancer, where it is often linked to more aggressive disease. It is particularly prevalent in high-grade serous ovarian cancer (HGSOC), where it is identified in approximately 20% of cases and is a primary driver of the tumor’s growth. This alteration is also frequently observed in certain aggressive forms of breast cancer, particularly triple-negative breast cancer.
Beyond gynecological cancers, CCNE1 amplification is found in a subset of gastroesophageal cancers, including those of the stomach and esophagus. Studies have identified this amplification in about 4-7% of these tumors, where it is associated with a specific molecular subtype characterized by chromosomal instability. Endometrial cancer, specifically the aggressive uterine serous carcinoma subtype, is another cancer where CCNE1 amplification is a recurring finding.
Treatment Implications and Targeted Therapies
The presence of CCNE1 amplification in a tumor often indicates a poorer prognosis and can predict resistance to standard treatments. For instance, in ovarian cancer, CCNE1 amplification is associated with resistance to platinum-based chemotherapy, a frontline treatment. This resistance is partly because CCNE1 amplification and mutations in the BRCA genes, which confer sensitivity to platinum drugs, are mutually exclusive.
This has spurred the development of targeted therapies, which are drugs designed to attack specific molecular vulnerabilities in cancer cells. For CCNE1-amplified cancers, a direct approach is to inhibit its partner protein, CDK2. Several selective CDK2 inhibitors, such as INX-315, are in clinical development and have shown promise in preclinical models by halting the uncontrolled cell cycle progression driven by excess Cyclin E1.
Another strategy involves targeting other proteins that the cancer cell becomes dependent on due to the stress caused by CCNE1 amplification. WEE1 inhibitors, such as adavosertib, are one such class of drugs. These inhibitors block a checkpoint that cancer cells use to repair DNA damage, and they cause the cells with high replication stress to die. Similarly, inhibitors of ATR and PKMYT1 are also being explored, often in combination, to exploit the genomic instability inherent in these cancer cells.
PARP inhibitors, a class of drugs effective in cancers with BRCA mutations, have been less effective in CCNE1-amplified tumors. However, research is ongoing to see if they could be effective when combined with other targeted agents. For many patients, accessing these novel treatments involves participation in clinical trials, which are investigating the safety and efficacy of these new therapeutic strategies for CCNE1-amplified cancers.