Epigenetics Plays a Major role in Breast Cancer Resistance

Breast cancer’s ability to develop resistance to treatment has frustrated researchers and physicians and has thwarted even the latest and greatest targeted therapies. For example, after researchers identified a disease pathway integral to many breast cancers called PI3K, they began testing experimental drugs that block this pathway — only to see the tumors activate another way to fuel their growth.

  However, a team of researchers led by scientists at Memorial Sloan-Kettering Cancer Center (MSK) have identified, for the first time, an epigenetic mechanism promoting breast cancer. The findings from this study were just released in the latest issue of Science through an article entitled “PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.”

    In the current study, the researchers found that inhibition of the PI3K pathway led to the activation of ER-dependent transcription through the epigenetic regulator KMT2D. These findings provide a rationale for epigenetic therapy in patients with PIK3CA-mutant, ER-positive breast cancer. While epigenetic factors have been known to play an essential role in various cancers, such as leukemia and lymphoma, this is the first evidence found in breast cancer.

    “This work perfectly shows how clinical observations drive fundamental research. We can ask relevant questions and form hypotheses based on real people and in real time,” explained senior study investigator Jose Baselga M.D., Ph.D., the physician in chief and CMO at MSK. “The discovery of a link between epigenetics and the PI3K pathway in breast cancer is another important piece of the puzzle. Understanding the mechanisms of the two important signaling pathways—ER and PI3K—will allow us to explore new therapeutic targets and combination treatment approaches for this patient population.”

    Estrogen-receptor-positive (ER-positive) breast cancer is one of the most common types of breast cancer, accounting for 70% of all cases. A common oncogenic mutation found in ER-positive breast cancers is in the gene called PIK3CA, which encodes the catalytic subunit of PI3K. This kinase coordinates essential cellular functions, including growth, survival, and tumorigenesis. Approximately 40% of all ER-positive breast cancers have PIK3CA mutations.

    PI3K inhibitors have shown effective antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. However, some recently emerged resistance mechanisms that could potentially limit their efficacy. Researchers have been working to understand the early adaptive responses that may mediate resistance to PI3K inhibitors in breast cancer. Scientists have observed that a highly uniform tumor response to PI3K inhibitors is characterized by an activation of ER-dependent transcription that drives tumor growth and limits the drugs’ therapeutic efficacy.

    These findings have paved the way for two large-scale Phase III clinical trials currently testing the combination of a PI3K inhibitor with anti-ER therapies, in which researchers have observed encouraging clinical activity. If the trials continue to show positive results, the combined inhibition of PI3K and ER could become the new standard of care for metastatic PIK3CA-mutant, ER-positive tumors. However, the underlying mechanisms leading to the robust activation of ER upon PI3K inhibition have yet to be discovered.

 While preliminary clinical trial results are showing promise, the MSK researchers set out to determine the biological mechanisms behind these successes. Using high-throughput epigenetic assays, the scientists could study for the first time the global epigenetic landscape of breast cancer cells from patients treated with PI3K inhibitors in clinical trials at MSK. Knowing that ER regulates genes as a transcription factor, researchers utilized high-throughput assays and found that it cooperates with other transcription factors. This “transcription factor regulatory network” is a group of elements that work together to mediate growth and require epigenetic marks. These marks are catalyzed by an epigenetic regulator called KMT2D. KMT2D is essential for cell maintenance, differentiation, and development.

    With the assays, the researchers identified KMT2D as the critical determinant of ER activation by the PI3K signaling pathway. The involvement of KMT2D in activating ER was confirmed through necessary patient biopsy samples. Further work confirmed that if KMT2D was removed, the ER activation that had previously been seen when the PI3K pathway was inhibited was no longer happening. In mice-bearing tumors, the authors confirmed that genetically removing KMT2D and inhibiting the PI3K pathway achieved higher tumor shrinkage than either therapy alone.

    “Over the past few years, we have learned that epigenetic mechanisms play a critical role in the initiation, development, and progression of many types of cancer, including lymphoma and some leukemias, although we have never seen it in breast cancer,” noted lead study investigator Eneda Toska, Ph.D., a research fellow in Dr. Baselga’s laboratory. “Now that we have identified a new mechanism directly connecting an oncogenic signaling pathway with epigenetic regulation in ER-positive breast cancer, we can explore the possibility of targeted and personalized therapies with a more limited chance of resistance in this setting.”