Towards personalized treatment for early stage HER2-positive breast cancer

One of the foremost reasons for resistance of breast cancers to HER2-targeted therapy relates to the lack of complete survival dependence of all tumour cells present in the patient on HER2 signalling. This phenomenon could be attributed to intratumour HER2 heterogeneity, whereby both HER2-amplified and non-amplified tumour cell populations co-exist within a clinically HER2-positive (HER+) tumour. While the HER2-amplified and addicted cells of such heterogeneous tumours can be effectively eradicated using biological anti-HER2 agents, including antibody–drug conjugates (ADCs) that target the HER2 receptor and deliver a cytotoxic drug specifically to the HER2+ cells, the non-HER2-amplified cells will continue to thrive, ultimately manifesting as treatment resistance. For tumours with intratumour HER2 heterogeneity, continued use of chemotherapy together with anti-HER2 therapy is required, until the alternative molecular drivers are elucidated. In tumours with homogeneous HER2-amplification, resistance to HER2-targeted therapy can arise owing to alterations in the HER signalling pathway itself or the activation of alternative bypass signalling pathways supporting cell survival or proliferation. Mutations affecting HER2 itself (such as the activating L755S mutation) or the downstream kinase PI3K (encoded by PIK3CA) and/or low levels of the inhibitory protein PTEN– provide mechanisms by which survival and proliferative signalling through the HER family receptors or their downstream pathways can be reactivated. Aberrations of HER2 that generate alternative forms of the receptor, such as the truncated protein p95HER2 and the splice variant Δ16HER2, can also mediate resistance to HER2-targeted therapies through loss of the epitopes recognized by therapeutic antibodies or by promoting dimerization and thus constitutive signalling. When the HER receptor network is effectively inhibited, however, resistance can arise owing to the emergence of several genomic and adaptive ‘escape’ mechanisms. These include crosstalk with transcription factors, such as the oestrogen receptor α (ERα),, activation of alternative cell-surface receptors (including other receptor tyrosine kinases (RTKs) or β-integrin)–, amplification of signalling adapter proteins (for example, those of the insulin receptor substrate (IRS) family,) or alterations in components of downstream signalling pathways, such as SRC and FAK. Resistance can also be caused by upregulation of membrane-associated mucin glycoproteins, which can interact with HER2–HER3 complexes and/or can mask the extracellular regions of HER2 and thus restrict the accessibility of this protein to drugs, particularly monoclonal antibodies,. Additionally, proliferative signalling can originate from metabolic pathways, such as the fatty acid synthesis, and mevalonate pathways,, supporting the survival and the emergence of resistance to therapy in tumour cells. Finally, tumour immune infiltrates, including lymphocytes, natural killer (NK) cells and dendritic cells, have also been reported to modulate responses and resistance to HER2-targeted therapy–.

Publication

Towards personalized treatment for early stage HER2-positive breast cancer. () Kristina Goutsouliak, et al. Nat Rev Clin Oncol. ;17(4):233-250. Figure: F2. All organisms Homo sapiens Drosophila melanogaster

Disease mentions