In the search for new approaches to treat ERBB2 (also known as HER2) positive breast cancers that have become drug-resistant, researchers found that ERBB4 (also known as HER4) is a driver protein in ERBB2-positive tumors that have developed resistance to first- or second-line treatments. These findings were published in Cell Cycle (2015; doi:10.4161/15384101.2014.994966).

“Approximately 25% of breast cancers overexpress and depend on the protein ERBB2 for survival,” said lead investigator Manabu Kurokawa, PhD, of the Norris Cotton Cancer Center of the Geisel School of Medicine at Dartmouth in Lebanon, New Hampshire.

“Current therapies take advantage of this by using targeted drugs such as trastuzumab or lapatinib to specifically inhibit ERBB2, but eventually they become ineffective as the cancer develops resistance to those drugs.”

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After seeing that pan-ERBB inhibitors remain effective against ERBB2-positive breast cancer cells with acquired resistance to anti-ERBB2 drugs, they used siRNA knockdowns of individual ERBB members to identify ERBB4 as crucial for the survival of resistant, but not naïve, ERBB2-positive breast cancer cells. Then, they confirmed the importance of ERBB4 via immunohistochemistry analysis of lapatinib-resistant tumors in mice.

The role of ERBB4 in breast cancer has been controversial. Some studies say that ERBB4 does not play a role in breast cancer, and others have even suggested that it has anti-proliferative effects.

“We have shown that when ERBB2-postive breast cancers develop resistance to anti-ERBB2 drugs, they shift their dependence from ERBB2 to ERBB4, which acts as a new driver of cancer survival and proliferation,” explained Kurokawa.

The discovery of ERBB4 as a driver protein in ERBB2-positive cells with resistance to anti-ERBB2 drugs suggests that anti-ERBB4 drugs would be highly beneficial to patients who no longer respond to first- or second-line treatments.

“Identifying a cancer driver is crucial for cancer treatment because it allows the use of targeted therapies, which have less side effects than conventional chemotherapy drugs, against a particular protein,” said Kurokawa.

The next step for Kurokawa’s team is to elucidate the mechanisms by which ERBB2-positive breast cancers shift their dependence from ERBB2 to ERBB4. The PI3K/AKT pathway is a suspect, and its well-known links to cellular proliferation and survival may be connected to mediating the change at the cellular level.