HER2 Inhibitors

HER2 Inhibitors Mechanism of Action
Trastuzumab, Pertuzumab Anti-HER2 antibody inhibits HER2- receptor driven cell proliferation and survival by interfering with HER2 dimerization
Lapatinib Blocks EGFR and HER2-dependent cell proliferation and survival by inhibiting their kinase activity
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  1. Amplification of the HER2 gene results in higher expression of the HER2 protein, and activation of downstream signaling.
  2. HER2 signaling turns on both the KRAS and PI3K pathways, leading to increased tumor cell growth and survival.
  3. PI3K is comprised of two subunits: PIK3R1, the regulatory subunit and PIK3CA, the catalytic subunit with kinase activity. Growth factor binding to receptor tyrosine kinases causes PI3K activation by dissociating PIK3CA from PIK3R1. When PIK3CA is mutated, PI3K is active without growth factor stimulation or ligand-independent HER2 activation.
  4. PTEN acts as a negative regulator of PI3K pathway activity. Loss of PTEN protein or function results in unchecked activity of this pathway and cell growth without growth factor receptor stimulation.

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Green squares, sensitivity markers. Red squares, resistance markers