New Therapy Targets Aggressive Chemotherapy-Resistant Breast Cancer

One of the hardest cancers to treat are tumors in the breast that do not express receptors for estrogen, progesterone, and human epidermal growth factor, dubbed triple negative breast cancers (TNBCs). Nearly 15% of all breast cancers diagnosed are TNBC. Resistant to conventional chemotherapy, TNBC is closely associated with relapse progression to stage 4 of the disease where the tumor metastasizes.

“Triple negative breast cancer is particularly challenging to treat because of the limited options beyond chemotherapy. There are fewer targeted therapies compared to other types of breast cancer. Many triple negative breast cancers also do not respond completely to our best chemotherapies for reasons that we are still trying to understand fully but cancer stem cells play an important role in this resistance,” says Hanna Irie, MD, PhD, associate professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai.

Earlier studies show breast cancer stem cells (BCSCs) are responsible for the initiation, progression and spread of TNBCs and contribute to resistance to chemotherapy. Therapies that eliminate these stem cells could therefore improve outcomes for high-risk patients, potentially leading to complete remission.

“Cancer stem cells are relatively quiescent and proliferate more slowly compared to non-stem cell cancer cells. Therefore, they escape the effects of chemotherapy, many of which rely on cell division to work, and persist.  Cancer stem cells also have ways to pump out chemotherapy drugs. Cancer stem cells also have ways to avoid recognition by immune cells, which can compromise immunotherapies,” explains Irie.

In a new paper titled, “Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease“  published in Nature Communications, Irie and a team of scientists report that they have identified and validated of a new breast cancer therapy that targets and eliminates breast cancer stem cells.

“This study shows an exciting new therapeutic compound (108600) that can overcome chemotherapy resistance of triple negative breast cancer by targeting cancer stem cells that can drive this resistance. The study also shows how this drug can block and kill triple negative breast cancer that has already spread to other parts of the body, giving hope that this could be effective treatment for patients living with stage 4 triple negative breast cancer,” says Irie, co-corresponding author on the study.

Estrogen receptor, progesterone receptor, and human epidermal growth factor oncogene HER2 are commonly used to classify breast cancer subtypes. TNBC that do not express these major molecular markers cannot be treated using conventional hormone- or HER2-directed therapies.

There are few FDA-approved targeted approaches for patients with this aggressive form of the disease. Current treatment for most early stage TNBC is a combination of surgery, radiation and chemotherapy. Treatment for advanced TNBC is mostly chemotherapy, although recent approvals for immunotherapy and antibody-drug conjugates have been exciting new additions, says Irie.

TNBC disproportionately affects younger, premenopausal women, women with inherited mutations in the BRCA1 gene, and Black women—a group that has an alarming 40 percent higher rate of breast cancer mortality in the U.S. Therefore, the lack of adequate treatments is particularly concerning.

In this study, the authors identify a new multi-kinase inhibitor (108600) that targets and inhibits breast cancer stem cells by inducing programmed cell death (apoptosis). The team identified 108600 by screening for drugs in a compound library to identify those that kill breast cancer stem cells.  The new compound overcomes chemotherapy resistance in patients with triple negative breast cancer.

“A targeted therapy inhibits specific molecules—usually molecules that are hyperactivated in cancers and which cancer cells rely on for growth more than normal cells,” explains Irie.

In mouse models generated from patient cancers, 108600 in combination with chemotherapy eliminates aggressive triple negative breast cancer, even those that have already spread to other regions of the body.

“108600 suppresses the growth of  tumor grafts derived from patient cancers that responded poorly to standard chemotherapy like Paclitaxel,” says Premkumar Reddy, PhD, professor at the  Departments of Oncological and Pharmacological Sciences and director at Experimental Cancer Therapeutics, at Icahn School of Medicine at Mount Sinai. Reddy is co-corresponding author on the study.

“108600 as a single agent or in synergistic combination with chemotherapy dramatically inhibited growth of these chemotherapy resistant tumors by decreasing the BCSC population within these tumors,” says Reddy.

Once translated to an early phase clinical trial, 108600 has the potential to improve survival and quality of life for patients diagnosed with triple negative breast cancer.