Table 1.

Proposed mechanisms of Herceptin Resistance.

Methods of Resistance	Protein	Mechanism
Epitope Masking	MUC41	Disrupts binding of Herceptin to Her2
	CD44	Binding to hyaluronan activates PI3K/Akt2
	p95Her2 (truncated form of Her2)	Dimerizes with Her3 to interfere w receptor-antibody binding
Upregulation of Her2 downstream signals	PTEN3 mutation	Loss pf PTEN allows PI3K activation
	PI3K mutation	Disrupts binding of Herceptin with Her1/Her3/PI3K allowing Akt activation
	PDK14	Akt signaling
Overexpression of Her family members	Her1, Her3, EGFR 5, ErbB2	Increased MAPK6, PI3K signaling
Overexpression of Her ligands	TGF-α7, EGF8, heregulin	Activation of PI3K
Alteration of ADCC9	Impaired immune-mediated mechanism	Interferes with Herceptin-mediated ADCC

¹mucin-4 protein;

²Phosphatidylinositol 3-kinase/protein kinase B;

³Phosphatase and tensin homolog;

⁴Phosphoinotiside-1;

⁵Epidermal growth factor receptor;

⁶Mitogen-activated protein kinase;

⁷Transforming growth factor-α;

⁸Epidermal growth factor;

⁹Antibody-Dependent Cell-Mediated Cytotoxicity