30 years after the discovery of the HER3 cell growth regulator, scientists have now discovered a HER3-directed small molecule inhibitor called AC3573, which, upon becoming a clinical candidate, could serve as the basis of a new cancer treatment. The study, which was published in the Biochemical Journal, was conducted by a collaboration between Francis-Crick Institute, AstraZeneca, Kings College London and CLF. It included microscopy scientists Dr Laura Zanetti-Domingues and Dr Selene Roberts, and data scientists Dr Michael Hirsch and Dr Dan Rolfe in the group of Marisa Martin-Fernandez. Using the CLF's advanced laser microscopy systems, the mechanism behind the new compound was revealed.
HER2 and HER3 are oncogenes that are members of the epidermal growth factor receptor (EGFR) family. HER2 and HER3 need to associate with each other to initiate cellular growth. Overexpression or mutation can lead to cascade events that induce hyperactivity, which can lead to the development of aggressive breast cancers. Previous work from the collaboration has shown that a well-established HER2-targeting breast cancer drug, lapatinib, can sometimes paradoxically boost the growth of tumour cells in vitro (read about this here).
HER3 functions as a pseudokinase, which means it doesn't have any catalytic activity by itself, but it does play an active role in regulating signalling pathways once bound to HER2. This new study aimed to identify a small molecule that would disrupt the HER2/HER3 interaction with a view to impacting HER2-dependent cancer progression.
Audrey Colomba led the team in analysing over 100,000 compounds from AstraZeneca as candidates for inhibiting HER3 activity. Via this screen and subsequent cell-based analyses, AC3573 was found to inhibit the formation of a HER2-HER3 heterodimer.
Using quantitative, nanoscale imaging available at the Octopus Imaging Cluster in the CLF, Laura Zanetti-Domingues and Selene Roberts studied what effect lapatinib and AC3573 have in cells on HER2/HER3 associations. In the first round of experiments Laura used Single Molecule microscopes and worked with Dan Rolfe to perform tracking and co-localisation analysis on the resulting images. This demonstrated a lower association between HER2 and HER3 receptors with AC3573 treatment.
Following the first round of experimentation STochastic Optical Reconstruction Microscopy (STORM) data taken by Selene revealed that AC3573 binding to HER3, in a breast cancer cell line called SKBR3, induces structural changes that prevent the formation of the HER2-HER3 complex. Dr Michael Hirsch (Octopus data scientist) conducted the cluster and co-localisation analysis on STORM images of both HER2 and HER3 receptors, which confirmed the neutralizing effect of AC3573. Michael's analysis showed that AC3573 indeed reduces active HER2-HER3 interactions in cancer cells, but, unlike lapatinib, has no effect on basal HER2.
Further experimentation will be conducted into this particular research area; however, this proof-of-concept study highlights the relevance of alternative HER3-mediated pharmacological therapies that could help fight aggressive breast cancers.
The full publication is available to view in the Biochemical Journal.
