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 resistanceMoleculeRole in cell growthRole in TZMB resistanceTherapeutic interventionReferences

De novo or
genetical resistance
PTEN Inhibition of PI3K pathways and control of cell growthMutated PTEN unresponsive to TZMB, constitutive activation of PI3K pathwaysiRNA inhibition of Akt[37, 40]
PIK3CA Encoding PTEN-resistant catalytical subunit of PI3KPI3 unresponsive to PTEN, constitutive activation of PI3K pathwaysiRNA inhibition of Akt[38, 41]
P95HER2 Truncated HER2 with kinase activityHER2 cleavage blocked by TZMBRTKs inhibitor: lapatinib[32, 39]
P27 CDK2 inhibition and cell cycle arrest in G1Induction of cell growth upon p27 inhibition or mutationp27 overexpression, proteasome inhibition, CDK2 inhibition[40, 42]

Acquired resistance (shaped by
compensatory kinase signaling pathways)
MUC4 Inhibition of immune recognition, HER2 activationHER2 masking from TZMB, induction of HER2 phosphorylationRTKs inhibitor: lapatinib[4345]
HER family members (RTKs) Heterodimerization with Her2 and activation of growth signaling pathwaysRTKs activation of alternative signaling pathways bypassing HER2Bispecific Abs or TZMB combined with other mAbs against RTKs[4650]
Alternative signaling pathwaysRETGDNF-mediated activation of PLC cell growth pathwayCrosstalk with HER2 via SRC activation, cross talk with MetConcomitant use of TZMB and siRNA against RET and/or SRC[51]
FAKBCSC growth by activation of Crk/CAS growth pathwayCrosstalk with HER2 via SRC activationCombination of TZMB and SiRNA against SRC[52]
MetCell mitogenesis and morphogenesis by activation of MAPK growth pathwayCrosstalk with HER2 via SRC activationCombination of TZMB and SiRNA against SRC[53]
EREstradiol-mediated growth by activation of PLC pathwayCrosstalk with RET and with HER2 via Src activationConcomitant use of TZMB, Tamoxifen, and SRC-SiRNA[5456]