Abstract LB-C11: HTLV-1 Tax-induced apoptosis to counteract tumor drug resistance

Abstract

Abstract p53 mutations have been identified in over 50% of human cancers. As p53-mutant tumor cells have an inherent resistance to therapy-induced apoptosis, such a mechanism of resistance is an important problem in cancer therapy. Interestingly, Tax, a protein expressed by the human T-cell lymphotropic virus type 1 (HTLV-1), increases the sensitivity of p53-mutant and p53-null cells to DNA-damaging drugs. Tax-induced chemosensitivity presents therefore a novel strategy that can be exploited to counteract p53-mutant tumor resistance. The objective of this work is to harness the chemosensitizing property of Tax and use it to develop a chemotherapeutic approach that can overcome the drug resistance observed in p53-mutant/p53-null cancers. We hypothesize that Tax initiates a proapoptotic response in cancer cells by modulating cyclin-dependent kinase 4 (CDK4) activity. We use a combination of in vitro and in silico analyses to determine the mechanism of Tax-induced chemosensitivity and to identify small molecules that can phenocopy the CDK4-activating and the proapoptotic effects of Tax. Immunoblot analyses and in vitro kinase assays reveal that Tax alters CDK4 expression and activity. In addition, flow cytometry and gene expression studies respectively indicate that Tax expression promotes G1-to-S phase transition and leads to increased expression of the TP73 gene, a known homolog of TP53. Moreover, our in silico analyses, using an N-terminal construct of Tax and a published structure of CDK4 (PDB 3G33), reveal that CDK4 interacts with the Tax construct via a C-terminal domain that is distinct from its nucleotide-binding and D-type cyclin-binding sites. Further analyses identify ten small molecule mimics of Tax and putative CDK4 activators, which we show have a proliferative effect on treated cells. Although the focus of ongoing studies in the field has been the development of kinase inhibitors, several tumors develop strategies allowing them to override the effect of those inhibitors. Our work adopts a different strategy that will maximize the cytotoxic effect of anticancer drugs to overcome acquired drug resistance. Citation Format: Vanessa C. Ducas, Gary M. Kupfer. HTLV-1 Tax-induced apoptosis to counteract tumor drug resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C11.