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 (p85ErbB2) 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 p85ErbB2. Here we show that PUVA reduced p85ErbB2 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.
Highlights
Seeking to demonstrate the effects of PUVA on ErbB2 signaling, we showed that steady-state protein levels of the activated, phosphorylated form of ErbB2 were reduced in PUVA-treated ErbB2+ breast cancer cell lines in a dose-dependent manner (Figure 2)
We recently showed that development of acquired therapeutic resistance to the reversible HER2 and EGF Receptor (EGFR) tyrosine kinase inhibitor lapatinib in HER2+ breast cancer cells can be mediated by a number of mechanisms including: (i) a switch in the regulation of cell survival from HER2-HER3-PI3K signaling in treatment naıve cells to EGFR-HER3-PI3K in resistant cells [16]; Figure 2
T cells, which mediate many of the dermatological indications for PUVA e.g. graft-versus-host disease; cutaneous T cell lymphoma seem to be sensitive to the anti-proliferative effects of PUVA and have served as a Figure 4. 8MOP interacts with the catalytic kinase domain of ErbB2. (A) 8MOP interacts with three peptide regions within the ErbB2 catalytic kinase domain
Summary
8-Methoxypsoralen (8MOP) is a linear tricyclic molecule that readily enters cell nuclei where it intercalates DNA at pyrimidinepurine sites [1]. Gene amplification and overexpression of ErbB2, which occurs in 25% of all breast cancers, predicts for a poor clinical outcome as a consequence of increased tendency to metastasize to visceral organs earlier in the disease course [10,11] These findings have prompted the development of ErbB2 targeted therapies- biological and small molecule tyrosine kinase inhibitors (TKIs)- for the treatment of early and advanced stage ErbB2+ breast cancers [12]. We show that PUVA can trigger significant apoptosis in ErbB2+ breast cancer models of acquired therapeutic resistance to lapatinib and similar ErbB2 targeted therapies. These findings and their clinical implications will be further discussed
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