title: Photo-activated psoralen binds the ErbB2 catalytic kinase domain, blocking ErbB2 signaling and triggering tumor cell apoptosis.
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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America ; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Wenle
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Chemistry, Research Drive, Duke University, Durham, North Carolina, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Gooden
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Leihua
authors.initials: L
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Sumin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Research Drive, Duke University, Durham, North Carolina, United States of America.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Soderblom
authors.affiliation: Department of Chemistry, Research Drive, Duke University, Durham, North Carolina, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.affiliation: QNS Group, LLC, Bahama, North Carolina, United States of America.
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Beyer
authors.affiliation: Immunolight LLC, Detroit, Michigan, United States of America.
authors.forename: Harold
authors.initials: H
authors.lastname: Walder
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America ; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005363:Ficusin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000077341:Lapatinib; D058990:Molecular Targeted Therapy; D011701:PUVA Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D005363:Ficusin; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib