Laboratory studies suggest that mechanisms of resistance to tyrosine kinase inhibitor therapy differ between the specific subtypes of HER2-positive breast cancer.
Laboratory studies suggest that mechanisms of resistance to tyrosine kinase inhibitor (TKI) therapy differ between the specific subtypes of HER2-positive breast cancer. MET signaling is involved in basal-like cells, while HER2/HER3 heterodimerization plays a role in luminal-like HER2-positive cells.
The TKIs lapatinib and neratinib were recently approved by the US Food and Drug Administration for treatment of certain patients with HER2-positive breast cancer. “However, responses to these TKIs vary between patients and in advanced cancers are usually not durable,” wrote study authors led by James E. Korkola, PhD, of the Oregon Health and Science University School of Medicine in Portland.
A number of possible mechanisms of resistance to these agents have been proposed. The investigators examined how microenvironmental signals influence that resistance by monitoring TKI-treated HER2-positive breast cancer cells that were grown on microarrays composed of extracellular matrix proteins. The results were published in Cell Systems.
The microenvironment microarrays (MEMA) allowed the researchers to add soluble ligands to the cells, allowing them to assess how thousands of various microenvironmental signals affected them. In total, they tested approximately 2,500 combinations of more than 100 proteins on basal-like HER2-positive cells (HER2E), and on luminal-like HER2-positive cells (L-HER2+) that were treated with lapatinib or neratinib.
The researchers found that in HER2E cells, a ligand for MET known as hepatocyte growth factor (HGF) induced resistance to the TKIs. That effect could be reversed with crizotinib, which is an inhibitor of MET.
In contrast, the L-HER2+ cells had another primary mechanism of resistance. In those, the HER3 ligand neuregulin1-Î²1 (NRG1Î²) induced the resistance. In this case, that resistance could be reversed with pertuzumab, which is an inhibitor of HER2/HER3 heterodimerization.
“Our studies raise the possibility that responses to TKIs may vary between different anatomical metastatic sites since the levels of HGF and/or NRG1Î² expression differ between sites to which HER2-positive cancers may metastasize,” the authors wrote. “Our findings raise the possibility that clinical control of HER2-positive breast tumors with HER2-targeted TKIs lapatinib and neratinib may be improved by HER2-positive subtype-specific strategies to counter resistive microenvironmental signals.”