Though inhibited by a drug, a cancer-promoting cell receptor may stage a comeback, becoming part of a receptor–receptor pair that signals cancer cells to proliferate, should growth factors be present. This undesirable teamwork, which was uncovered by scientists at the Francis Crick Institute, may explain why lapatinib failed clinical trials as a standalone drug against breast cancer.

The scientists suggest that the drug-induced receptor–receptor effect they’ve found may do more than just uncover a potential drawback of lapatinib and drugs like it. The effect may also alert drug designers to a more general problem: Obscure protein interactions may lead to drug resistance.

Using a combination of biochemical, biophysical, and computer modeling tools, the Francis Crick team discovered that lapatinib causes human epidermal growth factor receptor 2 (HER2) on cell membranes to pair up with another protein of the same family, HER3. When these inhibitor-induced HER2–HER3 pairs encounter naturally occurring growth signals from outside of the cell, they can rearrange themselves into an active, signaling pair. In this state, the HER2–HER3 pair tells cells to divide, including breast cancer cells.

“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,” cautioned the Francis Crick Institute’s Jeroen Claus, Ph.D. “Determining these risk factors could help doctors decide which patients may benefit most from these drugs.”

Claus is the first author of a paper (“Inhibitor-Induced HER2-HER3 Heterodimerisation Promotes Proliferation through a Novel Dimer Interface”) that appeared May 1 in the journal eLife. This paper states that lapatinib, an adenosine triphosphate (ATP)-competitive inhibitor of HER2, can induce proliferation cooperatively with the HER3 ligand neuregulin. “This counterintuitive synergy between inhibitor and growth factor,” the paper points out, “depends on their ability to promote atypical HER2-HER3 heterodimerisation.”

Around 20% of breast cancers are caused by a massive excess of HER2, which sends signals telling cancer cells to grow and divide. Lots of treatments for HER2-positive breast cancer work by switching off HER2 to make the cells stop growing or die. They can do this from outside the cell (antibodies such as trastuzumab) or inside the cell (kinase inhibitors such as lapatinib). Lapatanib is one of many kinase inhibitors used to treat HER2-positive breast cancers, and HER2 is an important target for other existing and emerging breast cancer treatments.

“In recent patient 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,” noted Prof. Tony Ng, a clinician scientist heading the School of Cancer and Pharmaceutical Sciences at King’s College London (KCL), and joint senior author of the paper “Our new findings could help us design future studies to improve combined HER2 targeted therapies.”

“Although our study was in breast cancer cells,” added Prof. Peter Parker, joint senior author of the paper and group leader at the Francis Crick Institute and KCL, “it gives us new insights into the nuts and bolts of what happens to HER2 when you try to block it and raises some interesting questions around how we should approach designing drugs against HER2-positive breast cancer in the future.”

“Our results provide a potential molecular mechanism for the disappointing results observed in a recent Phase III study of lapatinib used in an adjuvant setting,” the article’s authors concluded. “These results indicate there are complicating factors in hindering lapatinib efficacy in patients, which may involve the expression levels of HER3 and neuregulin stimulation by a complex tumor microenvironment.”

“The complex relationships between distinct protein conformation dynamics, formation of oligomeric assemblies, the availability of ligand, and the various effects on downstream signaling all need to be considered when applying targeted therapy to avoid potentially unexpected enhanced cancer cell proliferation after inhibitor treatment.”








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