Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics

161Tumor cells with resistance to HER2 inhibitors can be prime targets for HER3-directed nanobiologics. Schematic summarizes several scenarios that may explain how drug-resistant tumor cells can be targeted by HER3-nanobiologics. In the first scenario, tumor cells with acquired resistance to HER2-targeted inhibitors are characterized by increased cell surface display of HER3, cornering these resistant cells for attack by the HER3-nanobiologics described here. These studies also suggest that pre-treatment of sensitive or naïve tumors may yield the same result by shifting naïve tumor cells to a HER3-elevated phenotype. In the second scenario, HER2-sensitive tumor cells in a heterogenous population may be eliminated, leaving resistant cells that could be vulnerable to nanobiologic attack due to increased cell surface display of HER3. The studies described here also suggest that such tumors with inherent or pre-existing resistance to HER2 inhibitors may likely have increased cell surface HER3, thus making them vulnerable to nanobiologic attack.