Abstract 4676: A novel APIM-motif comprising peptide drug potentiates the action of several chemotherapeutic drugs by blocking the interaction between PCNA and key proteins involved in DNA repair, apoptosis and cell cycle control
Authors: Marit Otterlei, Rebekka Muller, Toril Holien, Siri Backhe, Thea K. Våtsveen, Torstein B. Rø, Anders Sundan
Journal: Cancer Research (2012)

Abstract APIM is a 5 amino acids motif found to mediate interaction between a series of proteins and Proliferating Cell Nuclear Antigen (PCNA) (Gilljam et al. 2009). In addition to proteins essential for replication, PCNA interacts with many proteins involved in DNA repair, epigenetic, cell cycle control and apoptosis. While many housekeeping proteins interact with PCNA via the PIP-box sequence, many repair, cell cycle, epigenetic and apoptosis regulating proteins use the APIM-motif for interaction with PCNA. Our data suggests that when the replication or transcription of DNA is arrested due to DNA damage, or when the cells are in an activated/stressed state, the post-translational modifications on PCNA are altered in a way that catalyses a shift of a high affinity PCNA binding housekeeping set of proteins to proteins involved in damage and stress avoidance. Thus, the APIM-motif is used during a switch from normal to stressed conditions. By introducing the APIM-motif in a peptide sequence which is engineered to penetrate cells and enter the nucleus (ATX-101), many normal cellular stress responses are inhibited and cells are sensitized to cell death by apoptosis. In vitro experiments have shown that over-expression or addition of APIM-peptides increases the sensitivity of several cancer cells to a wide range of clinically relevant anti-cancer therapies including inter-strand crosslinkers, intercalating drugs, small molecule inhibitors of various signal transductions pathways, cancer antibiotics or stress-inducing agents. In some cancer cell lines and primary cancer cells from patients, e.g. multiple myeloma cells cultured “ex vivo” with and without Bone Marrow Stromal Cells (BMSC), ATX-101 induces apoptosis on its own whereas primary normal cells are far less affected by the peptide. This effect of ATX-101 is S-phase independent. In addition to inducing apoptosis as a single agent, ATX-101 increases the sensitivity to melphalan in these assays. Finally, we have obtained proof of concept in a multiple myeloma model in mice; these results showed that ATX-101 significantly increases the anti-cancer efficacy of melphalan in vivo in the absence of detectable toxicity. Thus, by targeting PCNA with ATX-101 in combination with different chemotherapeutic drugs, we can increase the therapeutic window of a given therapeutic drug used at its maximum tolerated dose, or alternatively, achieve the same levels of efficacy using sub-optimal drug doses. Ref.: Gilljam KM, Feyzi E, Aas PA, Sousa MM, Muller R, Vagbo CB, Catterall TC, Liabakk NB, Slupphaug G, Drablos F, Krokan HE, Otterlei M. 2009. Identification of a novel, widespread, and functionally important PCNA-binding motif. J Cell Biol 186(5):645-654. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4676. doi:1538-7445.AM2012-4676