An interdisciplinary team of UNC-Chapel Hill researchers from computational medicine, genetics, biostatistics and surgery studied how cell cycle flexibility allows cancer cells to breast cancer to escape the effect of anticancer drugs that target cell division. UNC Lineberger members Jeremy Purvis, Ph.D., professor of genetics, and Phillip Spanheimer, MD, assistant professor of surgery, conducted this study.
The results of research were published in Proceedings of the National Academy of Sciences.
How cancer cells escape drug therapies that treat breast cancer
Drugs that inhibit the tumor cell cycle, such as palbociclib, have helped treat patients with the estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2−) subtype of breast cancer. Although these drugs often improve patient outcomes, a small percentage of tumor cells survive and divide in the presence of palbociclib, a phenomenon known as fractional resistance.
It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes.
A team of researchers at UNC-Chapel Hill shows that fractional resistance results from cell-to-cell differences in central cell cycle regulatory proteins that allow a subset of cells to escape palbociclib therapy.
The team combined multiplex single-cell imaging to identify fractionally resistant cells in both cultured and primary breast cancer samples removed from patients.
Resistant cells showed premature accumulation of multiple cell cycle regulatory proteins as well as increased sensitivity to pharmacological inhibition of cyclin-dependent kinase 2 activity, which is another cell division program and another potential drug target.
Using computational approaches to trace the path of cancer cells through the cell cycle, the researchers show how flexibility, or plasticity, among cell cycle regulators gives rise to alternative cell cycle “pathways” that allow individual cancer cells to escape the treatment with palbociclib.
Understanding the factors that determine cell cycle plasticity and how to eliminate resistant cell cycle pathways could lead to improved cancer therapies targeting partially resistant cells. And improving such therapies would likely improve patient outcomes.
Resistance to HER2-targeted therapies can be a problem when treating patients with HER2-positive (HER2+) breast cancer. Therefore, the identification of new therapies for this patient group is important.
Researchers at the Leibniz Research Center for Work Environments and Human Factors in Dortmund (IfADo) have already shown that the EDI3 enzyme is associated with changes in the metabolism of tumor cells. Their latest findings reveal that EDI3 inhibition may be a novel therapeutic target in patients with therapy-resistant ER-HER2+ breast cancer.
Breast cancer tumor cells alter their metabolism to maintain growth, thus ensuring their survival. Enzymes regulate metabolism and are therefore valid candidates for targeted anticancer therapies. IfADo researchers have already identified one of these enzymes: EDI3.
The glycerophosphodiesterase EDI3, which cleaves glycerophosphocholine into choline and glycerol-3-phosphate, influences choline and phospholipid metabolism and has been linked to cancer-relevant functions in vitro. Although the importance of choline metabolism in breast cancer has been studied, the role of EDI3 in this type of cancer has not yet been explored.
In a recent study published in the Journal of Experimental & Clinical Cancer Research, researchers demonstrated that EDI3 expression is higher in ER-HER2+ breast tumors in humans and that both expression and enzyme activity were higher high in ER-HER2+ breast cancer cell lines. Silencing of HER2 and inhibition of HER2 signaling reduced EDI3 expression. Inhibition of EDI3, in turn, mainly reduced the viability of ER-HER2+ cells. Furthermore, inhibition of EDI3 in ER-HER2+ cells resistant to HER2-targeted therapy reduced cell viability in vitro and breast cancer growth in vivo in mice.
Based on these findings, the researchers conclude that EDI3 expression is upregulated in ER-HER2+ breast cancers compared to other subtypes. Furthermore, inhibition of EDI3 leads to a significant reduction in tumor viability and growth, particularly in ER-HER2+ breast cancer cells that are resistant to conventional HER2-targeted therapies. Targeting EDI3 could therefore represent a therapeutic approach to enhance the effect of standard therapies, or an alternative in case of resistance to standard therapies.
HER2 is the name of a growth factor receptor. Its task is to capture signals coming from outside the cell and transmit them inside the cell, thus stimulating cell division. If a patient has too much of the HER2 growth factor receptor, the tumor is called HER2+, a subtype of breast cancer.
Due to numerous growth signals, the tumor may divide uncontrollably. Determining HER2 status is important because there are drugs that specifically target HER2. Most HER2+ patients respond successfully to these drugs, but for some, resistance to therapy is a problem. Therefore, alternative treatments are needed for this subtype of breast cancer.
In addition to HER2 signaling, the hormone estrogen can also influence the growth of breast cancer cells. Estrogen attaches to binding sites (hormone receptors) in the cell, which then activate the expression of genes that promote cell growth. To determine whether a tumor is growing in a hormone-dependent manner, the proportion of cells and the amount of corresponding hormone receptors are often examined. The result is expressed by the indication ER+ (estrogen receptor positive) or ER- (estrogen receptor negative).
PIK3CA is a gene that produces an enzyme called PI3K, which is involved in many important cellular functions. When PIK3CA mutates, however, it can make the PI3K enzyme overactive and cause cancer cells to grow.
Researchers have long known that PIK3CA is one of the most commonly mutated genes in breast cancer, and recently published research shows that PIK3CA mutations also lead to therapeutic resistance in HER2-positive breast cancer.
“Many growth signals in breast cancer cells are mediated through receptors that span the cell membrane: one part of the receptor is outside the cell and the other inside,” explains researcher Elena Shagisultanova, MD, Ph. D., University Fellow of the Colorado Cancer Center and Assistant Professor of Medical Oncology at the CU School of Medicine.
“The HER2 receptor is made up of two parts: the part outside the cell interacts with growth factors and the internal part sends growth signals to the 'command center', the cell nucleus. PI3K is located immediately under the cell membrane and is connected to the HER2 receptor. So even if we are blocking HER2, PI3K can still send growth signals to the nucleus and the cancer cell will grow.
It's important to remember, says Shagisultanova, that HER2 and PI3K are necessary for cell development and growth, the kind of growth that occurs in normal tissues. However, “when it gets activated abnormally, all the systems of checks and balances get thrown out of balance, and that's when cancer starts.”
HER2 is a protein present in approximately 20% of breast cancers. HER2-positive breast cancers tend to be more aggressive than other breast cancers, although treatments designed to specifically target HER2 have proven to be very effective. Many of these treatments involve blocking HER2 growth signals.
“Since we discovered HER2 inhibitors, the life expectancy of patients with HER2-positive breast cancer has improved enormously, because we are able to block one of the main factors causing this cancer,” says Shagisultanova.
“If we only use chemotherapy and don't block HER2, the cancer cells divide faster than we can kill them, even with powerful chemotherapy. But once we block HER2 growth signals, the combination of that HER2 blocker and chemotherapy can kill tumor cells and cure patients with early-stage HER2-positive breast cancer or prolong the lives of patients with HER2-positive metastatic tumors .”
Approximately 30% of HER2 positive patients also have PIK3CA mutations. Because the PI3K protein is directly linked to the HER2 receptor, “if it is mutated and has been activated, no matter how much it blocks HER2 growth signals upstream, PI3K will still send the growth signal downstream and render our blockade useless,” explains Shagisultanova. “PI3K will tell cancer cells to grow.”
Now that evidence shows that PI3K drives therapeutic resistance in HER2-positive breast cancer, one of the next major research focuses will be the development of inhibitors for PI3K.
“It has been very difficult to develop effective inhibitors for this molecule because PI3K is linked to many growth factor receptors,” says Shagisultanova. “In initial studies we saw that when you block PI3K, insulin signaling tries to counteract this blockade and blood sugar rises. So, one of the side effects was diabetes, and we don't want to make cancer patients unnecessarily sick with other conditions during cancer treatment.”
In 2019, a second-generation PI3K inhibitor was developed that does not have high levels of toxicity. Through cell lines and animal models run in her lab, Shagisultanova was able to show that the recently approved PI3K blocker combined with a HER2 blocker regressed tumors, “which is very, very encouraging,” she says. “We saw that the result was the prevention of tumor growth.”
Shagisultanova has received FDA approval for a clinical trial in patients with HER2-positive metastatic breast cancer, expected to open later this summer. This research will study the combination of PI3K and HER2 blockers in humans.
“What we are trying to do is interrupt all growth pathways of tumor cells,” explains Shagisultanova. “We are confident that this combination of PI3K and HER2 inhibitors will show significant results for patients with this aggressive type of breast cancer.”
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