Table 2.
Drugs in development that target HER2 or pathways proposed to contribute or to mediate resistance to trastuzumab and/or lapatinib
| Drug | Mechanism |
| Pertuzumab | Humanized HER2 IgG1, binds to heterodimerization domain II |
| Trastuzumab-DM1 | Inhibition of microtubule polymerization (apoptosis) after internalization; ADCC |
| Irreversible HER2/EGFR TKIs (neratinib, BIBW-2992) | Covalent binding to ATP pocket in HER2 and EGFR |
| HER3 monoclonal antibodies (MM-121, AMG-888) | Block heregulin binding and partially downregulate HER3 |
| PI3K inhibitors (BKM120, GDC-0941, XL147) | ATP competitive inhibitors of p110 |
| Dual PI3K/TOR inhibitors (BEZ235, XL765) | |
| Rapalogs: everolimus (RAD001), temsirolimus (CI-779), ridaforolimus (MK-8669) | Non-catalytic inhibitors of TORC1 |
| Catalytic mTOR inhibitors (OSI-027, AZD8055) | Inhibit TORC1 and TORC2 |
| AKT inhibitors (MK-2206, AZD5363) | Allosteric or catalytic inhibitors of AKT1/2 |
| IGF-IR TKIs (OSI-906, AEW 541) | Inhibition of InsR and IGF-IR tyrosine kinases |
| IGF-IR monoclonal antibodies (MK-0646, R1507) | IGF-IR downregulation; inhibition of IGF-I binding to IGF-IR |
| HSP90 inhibitors | Induce degradation of HER2 and signal transducers |
| MET, Src, TGFβ inhibitors | Block mechanisms of resistance |
| MMP inhibitors | Prevent ectodomain shedding (HER2 cleavage) |