Overcoming CDK4/6 Drug Resistance in Breast Cancer

April 1, 2016
Lauren Evoy Davis

Resistance in estrogen receptor (ER)-positive breast cancer occurs in several ways, but preclinical studies suggest that changing the combinations of existing therapies may stave off resistance.

Researchers are finding news ways to delay resistance to cancer therapies. Resistance in estrogen receptor (ER)-positive breast cancer occurs in several ways, but preclinical studies suggest that changing the combinations of existing therapies may stave off resistance. Drugs such as palbociclib (Ibrance) are being used to target cyclin-dependent kinase 4/6 (CDK4/6) with some success, according to a study published in the journal Cancer Research.

“The CDK4/6 inhibitor palbociclib is now an important part of treatment for patients with ER-positive breast cancer,” said Nicholas C. Turner, FRCP, PhD, team leader at the The Institute of Cancer Research, London, and consultant at The Royal Marsden in London, United Kingdom, in an American Association for Cancer Research news release. “Unfortunately, most patients eventually have disease progression because their tumors acquire resistance to the anticancer agent.”

One of Dr. Turner's goals for his research team was to figure out how and why ER-positive breast cancer cells become resistant to CDK4/6 inhibitors so that the researchers could identify other drug combinations that might overcome a major barrier to wellness-drug resistance.

“Our preclinical studies identified a triplet therapeutic combination that could significantly delay the onset of resistance to CDK4/6 inhibitors, and this combination is being tested in phase II clinical trials. We also found that resistance arises through multiple mechanisms, suggesting that we will need to develop tests to identify the particular mechanism driving resistance in individual patients in order to determine the best treatment option post acquisition of resistance,” said Turner.

Collaborating with Violeta Serra, PhD, a principle investigator at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and a team of researchers, they tested approximately 3,530 compounds for their ability to work with the CDK4/6 inhibitor palbociclib to block the growth of ER-positive breast cancer cell lines in vitro. Some of the compounds inhibited the PI3K pathway. Next, they developed a patient-derived xenograft model, combining a CDK4/6 inhibitor, a hormone therapy (fulvestrant), and a PI3K inhibitor, which caused greater tumor regression compared with fulvestrant paired with either a CDK4/6 inhibitor or a PI3K inhibitor.

While PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. Researchers found that cells acquiring resistance to CDK4/6 inhibitors due to cyclin E1 (CCNE1)amplification could be resensitized by targeting cyclin-dependent kinase 2 (CDK2).

Further steps will include retesting these findings in the clinic to see if their findings translate from bench to bedside.

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