Abstract
The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR.
Highlights
Despite treatment advances and earlier diagnosis, breast cancer remains a major contributor to cancer morbidity and mortality
Expression of human epidermal growth factor receptor type 2 (HER2) on MDA-MB-231, MCF-7, SK-BR-3, and BT-474 cells had been determined [33, 34] to be approximately 8 Â 103, 1.5 Â 104, 1.9 Â 106, and 1 Â 106 receptors per cell, respectively. pIC/ PPHAffibody efficiently induced the death of HER2-overexpressing breast cancer cells as compared with low HER2-expressing cells, in a concentration-dependent manner (Fig. 1A)
PIC was selectively delivered into HER2-overexpressing cells, and cell death was induced in a HER2-dependent manner
Summary
Despite treatment advances and earlier diagnosis, breast cancer remains a major contributor to cancer morbidity and mortality. The human epidermal growth factor receptor type 2 (HER2) is amplified and/or overexpressed in 20% of breast cancers [1,2,3]. Overexpression of HER2 is associated with increased aggressiveness and significantly shortened diseasefree and overall survival [4,5,6,7]. Several targeted therapies have been approved for the treatment of HER2-positive breast cancer. These include the small molecular tyrosine kinase inhibitor (TKI) lapatinib, the humanized antibodies trastuzumab and pertuzumab, and the HER2-directed antibody–drug conjugate trastuzumab emtansine The most commonly used targeted therapy for HER2-positive breast cancer patients is trastuzumab (Herceptin), a humanized These include the small molecular tyrosine kinase inhibitor (TKI) lapatinib, the humanized antibodies trastuzumab and pertuzumab, and the HER2-directed antibody–drug conjugate trastuzumab emtansine (T-DM1; ref. 8).
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