We recently reported that the β1 integrin antagonist referred to as HYD1 induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this report we sought to delineate the determinants of sensitivity and resistance towards HYD1 induced cell death. To this end, we developed a HYD1 isogenic resistant myeloma cell line by chronically exposing H929 meyloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance towards HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1 and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised CAM-DR phenotype as demonstrated by increased sensitivity to melphalan and bortezomib induced cell death in the bone marrow stroma co-culture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens compared to newly diagnosed patients, a finding which correlated with α4 integrin expression. Collectively, these data indicate that this novel D-amino acid peptide may represent a good candidate for pursing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued pre-clinical development of HYD1 and analogs of HYD1 for the treatment of multiple myeloma and potentially other tumors which home and/or metastasize to the bone.
- Received March 9, 2011.
- Revision received August 24, 2011.
- Accepted September 16, 2011.
- Copyright © 2011, American Association for Cancer Research.