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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] |
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