Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids Elevated cell surface levels of the human epidermal growth factor receptor subunit 3 (HER3) is associated with resistance to a number of signal-blocking breast cancer treatments, including inhibitors of EGF-R (lapatinib), HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Additionally, HER3 elevation has been identified on “untarget-able” tumors such as triple-negative breast cancer (TNBC). Patients with such refractory tumors currently have limited treatment options and a poor prognosis. Moreover, as up to 70% of cases resist or acquire resistance to signal-blocking therapies, an alternative approach addressing this important clinical problem has the potential for significant clinical impact. We have developed a self-assembling nanobiological particle, HerDox, which uses HER3 as a portal for targeted entry of toxic molecules. In contrast to receptor-targeted antibodies and tyrosine kinase inhibitors currently used in the clinic, HerDox circumvents the need to modulate signaling and can induce rapid entry of toxic molecules into tumor cells by receptor- mediated endocytosis and membrane penetration. We have previously shown that HerDox can elicit targeted toxicity to trastuzumab-resistant HER2+ tumors due to the augmented levels of HER3 on these cells in association with resistance, while sparing heart and liver tissue. Whereas the prevalence of HER2-3 heterodimers on the HER2+ tumor cell surface can enable targeting by HerDox, naïve HER2+ tumors exposed to trastuzumab undergo acute shift to a HER3+ phenotype and acquire augmented sensitization to HerDox targeting and potency. EGFR inhibitors also have the same effect on both HER2+ and triple-negative breast tumors in experimental models. These findings suggest that neoadjuvant treatment of primary tumors with clinical inhibitors of HER2 or EGF-R can impart selective pressure on a heterogeneous tumor, driving expression of surviving cells to a HER3 augmented phenotype and thus cornering these resistant tumors for HerDox attack. This study will test this phenomenon in preclinical models of HER2+ and triple-negative tumors undergoing treatment with targeted therapies currently used in the clinic or in clinical trials that are aimed at HER2 and EGF- R, respectively. Our recent studies also show that HER3 is expressed on the blood-brain barrier (BBB) and can facilitate passage of systemic HerDox across the BBB and into brain-localized HER3+ TNBC tumors. The brain is a predominant site of metastasis for both TNBC and resistant HER2+ breast tumors, but most targeted therapies that are effective extracranially lack significant impact on intracranial tumors and thus brain metastases remain a significant clinical problem. Both HER2+ and TNBC tumors that escape intervention and metastasize to the brain express high levels of HER3. Therefore, we will also evaluate the therapeutic efficacy of HerDox on...