The ErbB family of receptor tyrosine kinases is well known to drug developers, though often under one of its aliases.

ErbB1, better known as epidermal growth factor receptor, or EGFR, is the target of drugs such as Tarceva (erlotinib, Roche AG and Astellas Pharma Inc.), Iressa (gefitinib, AstraZeneca plc.), Vectibix (panitumumab, Amgen Inc.) and Erbitux (cetuximab, Eli Lilly and Co.) Roche drugs Herceptin (trastuzumab), Perjeta (pertuzumab) and Kadcyla (trastuzumab emtansine) target ErbB2, which also goes by HER2/neu.

Now, researchers have presented evidence that a third family member, ErbB3, can also acquire activating or oncogenic mutations. In preclinical studies, antibodies targeting ErbB3 improved the survival of mice that had a leukemia-like disease after being implanted with ErbB3-mutant cells.

Given its family history, ErbB3 has been subject to less scrutiny than one might predict. It is the target of some drug development efforts – Merrimack Pharmaceuticals Inc. is in Phase II studies with its MM-121 antibody, and AVEO Pharmaceuticals Inc. has another antibody, AV-203, in Phase I. Others, including Roche unit Genentech, also are exploring its utility as a target.

But to date, there has been comparatively little effort made to see whether ErbB3 can acquire activating mutations that contribute to the initiation of cancer.

One reason is that ErbB3 has an impaired business end. Its kinase is mutated in such a way that it has very little activity, a fact that has led to "a degree of skepticism" about its potential role in cancer, Somasekar Seshagiri told BioWorld Today.

The attitude of many researchers was "why would you accumulate mutations in this protein, and why would it be a problem even if you do?"

"Sometimes," he added, "what seems obvious in hindsight is not so obvious when people are trying to focus," in terms of both attention and resources, on those areas that are most likely to yield a payoff in terms of therapeutic development.

Still, ErbB3 can combine with HER2, and the so-called heterodimers that are made up of one copy each of HER2 and ErbB3 play a role in HER2-driven cancers. Earlier studies had found that ErbB3 is overexpressed in some cancers, and that such overexpression correlates with a poor prognosis.

Together, those findings prompted Seshagiri, who is at Genentech, and his team to look at whether ErbB3 can also accumulate mutations that contribute to cancer development.

In their studies, which they published in the May 13, 2013, issue of Cancer Cell, the team sequenced the ErbB3 genes of more than 500 tumors, mainly of colorectal, gastric and non-small-cell lung cancers. They found that about 10 percent of colorectal and gastric cancers, as well as roughly 1 percent of lung tumors, contained activating mutations in the ErbB3 gene. The net effect of many of the mutations was that the ErbB3 receptor, which normally needs to be activated by binding ligand to dimerize with HER2, became ligand-independent.

In their studies, Seshagiri and his colleagues tested the effects of therapeutics targeting ErbB3, but also some that target HER2, EGFR or both, to see whether they killed ErbB3-mutant cells and affected the life span of mice with such tumors.

They found that in the specific models they tested, anti-ErbB3 antibodies improved survival of animals with activating mutations in ErbB3 – but so did Herceptin, which in some cases was more effective.

Seshagiri said the results suggested HER2-targeting drugs could be one weapon to fight ErbB3-mutated cancers. But it may still be worth it to go after such mutations directly. While ErbB3 often does interact with HER2, it also can combine with EGFR (and the other low-key member of the family, ErbB4).

"The jury is still out" on the best ways to go after ErbB3-mutated cancers, he said. But "it is clearly something we" – as well as others – "are looking into."