Drug resistance—when a cancer stops responding to a given treatment—presents a considerable challenge for doctors. It can develop any time during treatment, and it’s difficult to predict if or when it might occur and in which patients.
BCRF investigator Dr. Sarat Chandarlapaty’s research focuses on understanding why resistance happens in estrogen receptor (ER)–positive breast cancer. Recently, his team published a report in Cancer Cell about a novel tactic to potentially overcome breast cancer drug resistance in these patients, particularly those with metastatic breast cancer.
CDK4/6 inhibitors halt tumor cells’ growth cycle, promoting dormancy of these cells. Resistance can develop when these cells overcome dormancy and resume cell division. Dr. Chandarlapaty hypothesized that a tumor cell’s ability to start growing again involves a mutation in the p53 gene and that perhaps this is one underlying cause of resistance. His team devised studies to support this hypothesis.
“BCRF funding was critical from early on in this project, allowing us to investigate these findings in large cohorts of patients and numerous model systems so we could understand which specific cancers this is most relevant for,” Dr. Chandarlapaty said.
Read on to learn more about this study.
The cell cycle is a series of events that occur within a cell, enabling it to grow and divide. This process depends on effective cell signaling—the process whereby communication occurs within a cell directing it to grow or not. One way cell signaling occurs is through chemical modifications of specific proteins. These modifications result in a cascade of activity whereby other factors recognize the modification and are activated or dampened depending on type of modification. As this process continues, cells are instructed to perform specific tasks. But during the cell cycle, mistakes can happen. To prevent them from spreading, multiple cell cycle checkpoints help keep track of the entire process.
Cyclin-dependent kinases (CDKs) are proteins found in healthy and cancerous cells that control cell growth, including how quickly they grow and divide. They were discovered by BCRF investigator Sir Paul M. Nurse and others. CDK4/6 kinases are involved in cell signaling through the modification/phosphorylation of target factors, which direct the cell to proceed through the cell cycle. If there is damaged DNA as the cell grows, a cell cycle checkpoint stops cell growth, causing cell-cycle arrest or dormancy. Tumor cells, including those in the breast, can evade cell cycle checkpoints, causing increased activity in CDK4/6 kinases that lead to uncontrollable tumor cell growth. With this discovery, CDK4/6 inhibitors were developed to target CDK4/6 to prevent this.
ER-positive breast cancer is the most common subtype of the disease, and it can be effectively treated with standard-of-care endocrine therapy combined with CDK4/6 inhibitors. Researchers have shown that during prolonged treatment, some patients’ tumors can develop resistance to CDK4/6 inhibitors as tumors escape drug-mediated dormancy and resume growth. Further, this escape is facilitated by mutations in a known tumor suppressor gene, p53.
As previously mentioned, many cellular proteins and factors control the cell cycle. In fact, research has shown that specific proteins form a complex that acts as a gatekeeper. When assembled, the DREAM complex inhibits cell cycle genes and also causes cells to enter dormancy. Research has shown that a mutation in the p53 gene promotes tumor cells’ escape from dormancy by preventing the DREAM complex from assembling—thereby allowing dormant breast cancer cells to resume the cell-cycle process and continue to grow.
To understand why resistance emerges, Dr. Chandarlapaty’s team analyzed samples from thousands of patients with ER-positive breast cancer who received the combined therapy. They then correlated treatment response with mutations in the p53 gene.
The team found that patients with short-lived responses to CDK4/6 inhibitors had specific p53 mutations. In addition, they identified changes in one component of the DREAM complex (RBL2) in p53-mutated tumor models. Taking a closer look at how the complex is assembled, they found that RBL2 was phosphorylated.
This led them to examine another cell cycle protein involved in cell signaling through phosphorylation: CDK2 kinase. This kinase also allows the cell cycle to proceed and causes dormancy when inhibited. They suspect that, in p53-mutated tumors, CDK2 was responsible for the phosphorylation of RBL2, halting the assembly of the DREAM complex, and subsequently preventing tumor cells from becoming dormant.
Their hypothesis was supported as they showed CDK2 activity allows p53-mutated tumors to begin growing again. Since CDK2 inhibition results in dormant cells, they used p53-mutated laboratory models to test tumor response when both CDK2 and CDK4/6 were inhibited. Together, CDK2 and CDK4/6 inhibitors not only put p53-mutated tumors into dormancy, but cause a deep, irreversible, growth-arrested state.
These findings highlight the critical function of p53 and the DREAM complex in CDK4/6 inhibitors’ effectiveness. They also support potentially treating patients with highly selective CDK2 inhibitors, which are now entering clinical trials at Dr. Chandarlapaty’s institution.
If validated in clinical trials, these discoveries could potentially prevent CDK4/6 inhibitor resistance, which promotes ER-positive breast cancer metastasis. Research is ongoing to develop sensitive tests to identify more patients with specific p53-mutated tumors that may benefit from this new tactic, along with other potential strategies for reinforcing the growth-arrested state.
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