In around a third of ER-positive breast cancer cases, the tumors become treatment-resistant. Why is that?
These types of cancer are typically treated with drugs — such as tamoxifen and fulvestrant — that either lower the levels of the hormone or inhibit the estrogen receptors to prevent the tumors from spreading. This is known as endocrine therapy.
However, around a third of the people treated with these drugs develop resistance to them, which negatively impacts their chances of survival. The mechanisms that underlie the tumors’ resistance to therapy is not well understood and currently poses a major challenge.
Recently, however, specialists from the Dana-Farber Cancer Institute in Boston, MA, have made significant progress in uncovering what exactly happens in the bodies of people in whom endocrine therapy does not work.
Dr. Myles Brown — the director of the Center for Functional Cancer Epigenetics at the Institute — and his colleagues investigated how certain gene mutations render cancer cells more resilient, facilitating metastasis. Their findings, the scientists hope, may eventually lead to more effective approaches for patients who do not respond well to traditional treatments.
The results of the team’s study were published in the journal Cancer Cell.
In a previous study, Dr. Rinath Jeselsohn — who also co-led the new research — and former team saw that mutations of the estrogen receptor gene of cancer cells were largely responsible for the cancer’s resistance to treatment.
On that occasion, the scientists observed these mutations in the metastatic tumors of women who had received endocrine therapy and had not responded to it.
Following on from this discovery, Dr. Jeselsohn and her colleagues analyzed these mutations using laboratory models of ER-positive breast cancer, noting that they supported the cancer’s resistance to the drugs tamoxifen and fulvestrant.
The new study revealed additional mechanisms that researchers had not been aware of previously.
Besides enabling the tumors to adapt to estrogen deprivation, the genetic mutations were also responsible for activating genes that would allow the cancer tumors to spread even further.
Such mutations — which allow genes to gain surprising and novel functions — are referred to as neomorphic mutations.
Therefore, the effect of the genetic mutations is twofold, allowing the cancer tumor to undertake two distinct “lines of attack” at the same time.
“[E]ven though the drug therapies are selecting tumors that can grow without estrogen,” explains Dr. Brown, “the mutations also confer a metastatic advantage to the tumor.”
Once they noted the effects of mutations on breast cancer tumors, Dr. Brown and his colleagues turned to modern gene-editing tools — namely, CRISPR-Cas9 — to pinpoint exactly which genes were at the core of estrogen receptor-related alterations.
This revealed that one gene in particular, called CDK7, might lend itself well as a target for new cancer treatments. This gene normally encodes the enzyme cyclin-dependent kinase 7.
Dr. Brown and team took particular interest in the potential of this gene as a target since existing research has already found ways of blocking the expression of CDK7.
Nathanael Gray, also from the Dana-Farber Cancer Institute, experimented with an inhibitor for CDK7 a few years ago. This experimental inhibitor is called THZ1, and it showed potential as an aid for the drug fulvestrant.
The combination of fulvestrant and THZ1 was effective both in cell cultures of ER-positive breast cancer and in animal models of the disease, slowing down tumor growth significantly.
Dr. Brown and his colleagues believe that by putting two and two together, as it were, through the combined findings of all these studies led by the Dana-Farber Cancer Institute, specialists may be able to devise effective treatments for ER-positive breast cancers that don’t respond to endocrine therapy alone.
“These results support the potential of this combination as a therapeutic strategy to overcome endocrine resistance caused by the ER mutants,” the researchers suggest.
Dr. Joy and her colleagues are currently trying to develop appropriate CDK7 inhibitors, and they “hope to test these drugs and develop a clinical trial for patients with ER-positive metastatic breast cancer.”