A laboratory study has found that the HER2 inhibitor lapatinib used to slow HER2-positive breast cancer can actually induce tumor growth in some circumstances. The agent can promote an atypical form of HER2-HER3 heterodimerization, driving cell growth.
“In recent studies, HER2-targeted therapies that combined lapatinib with the antibody treatment trastuzumab successfully controlled HER2-positive breast cancers at first, but did not improve longer-term disease-free survival,” said study co-senior author Tony Ng, MD, PhD, of Kings College London, according to a press release. “Our new findings could help us design future studies to improve combined HER-targeted therapies.”
In the new lab studies, Ng’s group showed that lapatinib can cause HER2 receptors to cluster together in certain formations along with the pseudokinase HER3. The complex formed between HER2 and HER3 took a distinct form from the more commonly seen dimer of the two molecules, which is usually asymmetric in nature.
As a result of that atypical dimerization, the HER3 ligand neuregulin is activated. Neuregulin induces cell proliferation, meaning that when lapatinib is present, it can promote cell growth through the neuregulin response to the HER2-HER3 dimerization. “The synergy between growth factor and inhibitor requires an intricate, multi-step cascade of conformational events,” the authors wrote. The results of this work were published in eLife.
They note that these results could at least partially explain the disappointing results seen in the phase III ALTTO trial, in which adding lapatinib to trastuzumab failed to improve outcomes.
“If certain breast cancer drugs can cause cancer cells to grow more rapidly in particular circumstances in the lab, we need to evaluate carefully if that might happen in subsets of patients as well,” said Jeroen Claus, PhD, of the Francis Crick Institute in London, who was the study’s lead author. “Determining these risk factors could help doctors decide which patients may benefit most from these drugs.”