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HER2 signaling pathway, mechanism of action of targeted therapies, and resistance mechanisms. 1. The truncated P95HER2 isoform results in the loss of the extracellular binding site for trastuzumab. 2.–3. Overexpression of other tyrosine kinase receptors, such as IGF1-R and C-met, can continue to trigger downstream signaling despite blockade by trastuzumab. 4. Mutations or loss of PTEN constitutively activates the PI3K signaling pathway.
