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Chemical structure of the CDK4/6 inhibitor abemaciclib Photo: Dana-Farber Cancer Institute

Lab Study Shows Drug Combination Important to Overcome Drug Resistance in HER2 Metastatic Breast Cancer

A new study led by Dr. Shom Goel of the Dana-Farber Cancer Institute, and supported in part by BCRF demonstrated that new drugs called CDK4/6 inhibitors can overcome drug resistance in HER2-positive breast cancer.  While anti-HER2 drugs such as trastuzumab can halt the growth of these types of tumors, many patients’ cancers become resistant to these therapies, leading to a resurgence of cell growth and metastasis.

The study, reported in the journal Cancer Cell showed that adding a CDK4/6 inhibitor restored the sensitivity of HER2-positive tumors to the anti-HER2 drugs.

CDK4/6 inhibitors are a new class of targeted drugs that work by blocking the cell cycle, an important process in cell division that is often dysregulated in tumor cells, allowing them to divide uncontrollably. Early phase clinical trials in estrogen receptor-positive (ER+) breast cancer have shown promising results and Phase III studies are ongoing.

Using laboratory models of HER-positive breast cancer, the researchers showed that tumors resistant to HER2 blocking drugs had abnormally high levels of two proteins: cyclin D1 and CDK4. This finding led the investigators to test a combination of CDK4/6 inhibitors with HER2 blocking drugs. They found that the combination of abemaciclib (which inhibits CDK4/6) and HER2 blocking drugs significantly halted cancer cell growth in cell culture and delayed recurrence in mouse models.

“This result is particularly exciting as it leads us to speculate the CDK4/6 inhibitors might help patients with HER2-positive metastatic breast cancer and could potentially help in earlier stages of the disease where we aim to prevent recurrence of cancer,” stated Dr. Goel in the article.

Commenting on the study, BCRF investigator and Dana Farber researcher, Dr. Jean Zhao emphasized, “This study is a prime example of how we can apply what we learn in the laboratory to improve the treatment of patients.”

The mechanisms of drug resistance and how to prevent it are active areas of research among BCRF investigators. Our researchers are leading studies to identify markers to predict drug resistance to development and clinical trials testing of better treatment strategies, such as the combination described in the Dana Farber study.  The subject of drug resistance was the theme of the 2015 BCRF Annual Symposium and featured BCRF investigators Joan Brugge, Suzanne Fuqua and Vered Stearns.

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