Target Points in Trastuzumab Resistance

Table 1

Mechanisms of de novo and acquired trastuzumab resistance. BCSC: breast cancer stem cell; TZMB: trastuzumab; Ab: antibody; mAb: monoclonal antibody; RTK: receptor tyrosine kinase. See text for more details.

Type of resistance	Molecule	Role in cell growth		Role in TZMB resistance	Therapeutic intervention	References
De novo or; genetical resistance	PTEN	Inhibition of PI3K pathways and control of cell growth		Mutated PTEN unresponsive to TZMB, constitutive activation of PI3K pathway	siRNA inhibition of Akt	[37, 40]
	PIK3CA	Encoding PTEN-resistant catalytical subunit of PI3K		PI3 unresponsive to PTEN, constitutive activation of PI3K pathway	siRNA inhibition of Akt	[38, 41]
	P95HER2	Truncated HER2 with kinase activity		HER2 cleavage blocked by TZMB	RTKs inhibitor: lapatinib	[32, 39]
	P27	CDK2 inhibition and cell cycle arrest in G1		Induction of cell growth upon p27 inhibition or mutation	p27 overexpression, proteasome inhibition, CDK2 inhibition	[40, 42]
Acquired resistance (shaped by; compensatory kinase signaling pathways)	MUC4	Inhibition of immune recognition, HER2 activation		HER2 masking from TZMB, induction of HER2 phosphorylation	RTKs inhibitor: lapatinib	[43–45]
	HER family members (RTKs)	Heterodimerization with Her2 and activation of growth signaling pathways		RTKs activation of alternative signaling pathways bypassing HER2	Bispecific Abs or TZMB combined with other mAbs against RTKs	[46–50]
	Alternative signaling pathways	RET	GDNF-mediated activation of PLC cell growth pathway	Crosstalk with HER2 via SRC activation, cross talk with Met	Concomitant use of TZMB and siRNA against RET and/or SRC	[51]
		FAK	BCSC growth by activation of Crk/CAS growth pathway	Crosstalk with HER2 via SRC activation	Combination of TZMB and SiRNA against SRC	[52]
		Met	Cell mitogenesis and morphogenesis by activation of MAPK growth pathway	Crosstalk with HER2 via SRC activation	Combination of TZMB and SiRNA against SRC	[53]
		ER	Estradiol-mediated growth by activation of PLC pathway	Crosstalk with RET and with HER2 via Src activation	Concomitant use of TZMB, Tamoxifen, and SRC-SiRNA	[54–56]