1. Photo-activated psoralen binds the ErbB2 catalytic kinase domain, blocking ErbB2 signaling and triggering tumor cell apoptosis
- Author
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Neil L. Spector, Sumin Zhao, Wayne F. Beyer, Eric J. Toone, Wenle Xia, Erik J. Soderblom, David M. Gooden, Harold Walder, and Leihua Liu
- Subjects
Receptor, ErbB-2 ,medicine.medical_treatment ,Cancer Treatment ,lcsh:Medicine ,Apoptosis ,Biochemistry ,Receptor tyrosine kinase ,Targeted therapy ,chemistry.chemical_compound ,Catalytic Domain ,Drug Discovery ,Molecular Cell Biology ,Basic Cancer Research ,Molecular Targeted Therapy ,lcsh:Science ,skin and connective tissue diseases ,Psoralen ,Multidisciplinary ,Cell Death ,Kinase ,Ficusin ,Obstetrics and Gynecology ,Enzymes ,Cross-Linking Reagents ,Oncology ,PUVA therapy ,Quinolines ,Medicine ,Female ,Signal transduction ,medicine.drug ,Signal Transduction ,Research Article ,DNA damage ,Ultraviolet Rays ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Lapatinib ,Cell Growth ,Cell Line, Tumor ,Breast Cancer ,medicine ,Humans ,neoplasms ,PUVA Therapy ,Protein Kinase Inhibitors ,Cell Nucleus ,lcsh:R ,Proteins ,Radiobiology ,chemistry ,Drug Resistance, Neoplasm ,Small Molecules ,Cancer research ,biology.protein ,Quinazolines ,lcsh:Q - Abstract
Photo-activation of psoralen with UVA irradiation, referred to as PUVA, is used in the treatment of proliferative skin disorders. The anti-proliferative effects of PUVA have been largely attributed to psoralen intercalation of DNA, which upon UV treatment, triggers the formation of interstrand DNA crosslinks (ICL) that inhibit transcription and DNA replication. Here, we show that PUVA exerts antitumor effects in models of human breast cancer that overexpress the ErbB2 receptor tyrosine kinase oncogene, through a new mechanism. Independent of ICL formation, the antitumor effects of PUVA in ErbB2+ breast cancer models can instead be mediated through inhibition of ErbB2 activation and signaling. Using a mass spectroscopy-based approach, we show for the first time that photo-activated 8MOP (8-methoxypsoralen) interacts with the ErbB2 catalytic autokinase domain. Furthermore, PUVA can reverse therapeutic resistance to lapatinib and other ErbB2 targeted therapies, including resistance mediated via expression of a phosphorylated, truncated form of ErbB2 (p85(ErbB2)) that is preferentially expressed in tumor cell nuclei. Current ErbB2 targeted therapies, small molecule kinase inhibitors or antibodies, do not block the phosphorylated, activated state of p85(ErbB2). Here we show that PUVA reduced p85(ErbB2) phosphorylation leading to tumor cell apoptosis. Thus, in addition to its effects on DNA and the formation of ICL, PUVA represents a novel ErbB2 targeted therapy for the treatment of ErbB2+ breast cancers, including those that have developed resistance to other ErbB2 targeted therapies.
- Published
- 2013