HER2 therapy: Molecular mechanisms of trastuzumab resistance

Breast Cancer Research

Table 1 Proposed mechanisms of trastuzumab resistance

Mechanism	Example	References
Therapeutic agent cannot recognize molecular target: disrupted interaction between HER2 and trastuzumab	Overexpression of MUC4 sterically hinders antibody from binding HER2 surface receptor and may mediate cross-talk to activate HER2. Knockdown of MUC4 restored trastuzumab sensitivity of breast cancer cells in vitro	[26,27]
Compensatory signaling: increased signaling from HER family members	Growth factor ligands of EGFR, HER3, or HER4 (EGF, betacellulin, heregulin) reduced growth inhibitory effect of trastuzumab by 57, 84, and 90 percent, respectively. Trastuzumab binds domain IV of HER2 and domain II is involved in dimerization with ligand-activated family members; trastuzumab did not block heregulin-activated HER3/HER2 interaction in SKBR3 cells	[53,72]
Compensatory signaling: increased signaling from other receptor types	Overexpression of IGF-IR reduced trastuzumab-mediated growth arrest. Inhibition of IGF-I signaling by IGFBP3 increased sensitivity. IGF-IR interacts with and cross-talks to HER2 in trastuzumab-resistant cells but not in sensitive cells. Inhibition of IGF-IR increased trastuzumab sensitivity	[31-33]
Altered downstream signaling	PTEN deficiency correlated with resistance in clinical samples	[11]
	Increased Akt activity	[34,37]
	P27kip1 downregulation	[35,36]
Competition for binding therapeutic agent	Increased circulating HER2 ECD	[40]

ECD, extracellular domain; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-I binding protein; IGF-IR, insulin-like growth factor-I receptor; PTEN, phosphatase and tensin homolog deleted on chromosome ten.

ISSN: 1465-542X