Translucent image of a woman's torso showing triple negative breast cancer in one breast
Credit: Science Photo Library - ROGER HARRIS/Getty Images

Researchers at the Baylor College of Medicine have identified a protein called PKMYT1 as a promising marker for a form of drug-resistant breast cancer, as well as a potential drug target for patients that currently face a very poor prognosis.

Up to 80 percent of deaths from breast cancer are caused by estrogen receptor-alpha-positive (ER+) tumors. The standard treatment for this type of cancer is a combination of endocrine therapy and a CDK4/6 inhibitor. However, late-stage ER+ breast cancer patients with a mutation of the p53 tumor suppressor protein often develop resistance to this treatment.

“These patients have the worst prognosis of ER+ breast cancer patients,” said Charles Foulds, PhD, corresponding author and assistant professor at the Lester and Sue Smith Breast Center at Baylor College. “At this stage, the oncologist then will prescribe some form of chemotherapy as no targeted therapies yet exist. However, chemotherapy often is ineffective.”

In a study published in Molecular Cancer Therapeutics, Foulds and colleagues examined 22 patient-derived xenografts to investigate the proteins produced by drug-resistant ER+ breast cancer. In particular, they were looking at kinases. These are enzymes that often have elevated activity in cancer cells as compared to healthy cells.

A key advantage of studying kinases is that their three-dimensional structures are well-known, allowing pharmaceutical companies to design drugs that can block their activity. “There are roughly 80 small molecule inhibitors of kinases that have been FDA approved,” said Foulds.

The research group had previously developed a method called kinase inhibitor pulldown assay (KIPA) that can detect and quantify up to 300 kinases in a sample. Here, KIPA was used to compare the levels of kinases in tumors that don’t respond to endocrine therapy with tumors that do respond to this treatment. This allowed the researchers to identify the kinase PKMYT1 (membrane-associated tyrosine/threonine one) as a promising marker of treatment-resistant ER+ breast cancer.

To confirm this, the scientists measured the levels of PKMYT1 in patient samples and breast cancer cell lines. They found that high levels of PKMYT1 gene expression were associated with resistance to both endocrine therapy and CDK4/6 inhibition.

The researchers then went on to study the therapeutic potential of PKMYT1 as a drug target. Using patient-derived xenografts, organoids, cell lines and clinical samples, they studied the effects of a PKMYT1 inhibitor called lunresertib in combination with the chemotherapy drug gemcitabine.

The results revealed that the combination of lunresertib and gemcitabine significantly reduced the viability of tumor cells as compared to using the chemotherapy alone in ER+ breast cancer cells that were resistant to the standard treatment and had a p53 mutation.

According to Foulds, the group is already in the process of testing this combination therapy in another patient-derived xenograft model of drug-resistant ER+ breast cancer. If the results are positive, the aim is to set up a phase II trial with treatment-resistant ER+ breast cancer patients in collaboration with Repare Therapeutics and the research group of Cynthia Ma, PhD, at the Washington University.

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