Table II.

HER2 Targeting Agents and Mechanisms of Resistance

Agent	Target	Mechanism of Resistance	Factors Involved
Monoclonal Antibodies		Alterations in binding sites or tyrosine kinase domain Overexpression of alternative ErbB ligands and dimerization receptors Loss of downstream controllers Dimerization and interaction with other structurally unrelated receptors	p95HER2, MUC4 EGFR, ErbB ligands (TGFα, EGF, HB) PTEN IGF1R, MET
Trastuzumab Pertuzumab T-DM1	HER2 HER2 HER2
Tyrosine Kinase Inhibitors		Alterations in tyrosine kinase receptor domain Acquisition of new receptor mutations or molecular abnormalities in receptor signaling pathways Activation of further downstream signaling pathways	Extracellular mutations in the tyrosine kinase domain KIT and PDGFRA receptor signaling pathway PI3K-AKT, mTOR
Lapatinib (reversible) Neratinib (irreversible) Afatinib (irreversible) Canertinib (irreversible)	HER1, HER2 HER1, HER2, HER4 HER1, HER2, HER4 HER1, HER2, HER4
Inhibitors of Downstream Targets		Activation of further downstream signaling pathways	PI3K-AKT, mTOR, MEK, MAPK
Everolimus BKM120 BEZ-235 GS-1101 NVP-BKM120 GDC-0941 GSK458 GDC-0980 PI-103	mTOR PI3K/AKT PI3K/AKT/mTOR PI3K PI3K PI3K PI3K/mTOR PI3K/mTOR PI3K/mTOR
HSP90 Inhibitors		Up-regulation of alternative pathways	NF-kB, MAPK
Tanespimycin Retaspimycin AUY922	hsp90 hsp90 hsp90

Abbreviations: MUC4= mucin 4 cell surface associated glycoprotein, EGFR= epidermal growth factor receptor, TGF= transforming growth factor, HB= heparin binding, IGF1R= insulin-like growth factor-1 receptor, PDGFRA= platelet-derived growth factor receptor alpha polypeptide, mTOR= mammalian target of rapamycin, PI3K= phosphoinositide-3-kinase, AKT=protein kinase B, MAPK= mitogen activated protein kinase, HSP90=heat shock protein 90, HER=human epidermal growth factor receptor, PTEN= phosphatase and tensin homolog, T-DM1=trastuzumab-DM1, NF- kB= nuclear factor-kappaB