PARP inhibition; RTK inhibition; WTBRAF; melanoma; radiotherapy; Medicine (all); General Medicine
Abstract :
[en] Melanoma is known to be a radioresistant cancer. Melanoma radioresistance can be due to several factors such as pigmentation, antioxidant defenses and high Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene, Serine/Threonine Kinase (WTBRAF) melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in melanoma cell lines. PARP-1 inhibition by Olaparib or its KO mediates melanoma cell sensitivity to radiotherapy (RT). Similarly, specific inhibition of c-Met by Crizotinib or its KO radiosensitizes the melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on tumor growth inhibition but also on tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF melanoma.
Disciplines :
Oncology
Author, co-author :
Sabbah, Malak; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, Belgium
Najem, Ahmad; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, Belgium
Vanderkerkhove, Christophe; Medical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Kert, Fabien; Medical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Jourani, Younes; Medical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Journe, Fabrice ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service d'Anatomie humaine et Oncologie expérimentale ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, Belgium
Awada, Ahmad; Oncology Medicine Department, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Van Gestel, Dirk; Radiation Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Ghanem, Ghanem E; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, Belgium
Krayem, Mohammad; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, Belgium ; Radiation Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium
Language :
English
Title :
The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma.
M112 - Anatomie humaine et Oncologie expérimentale
Research institute :
R550 - Institut des Sciences et Technologies de la Santé
Funding text :
This study was supported by “L’Association Jules Bordet” and a Televie Grant No. 7651819F from the National Fund for Scientific Research (Belgium). Malak Sabbah is the recipient of a Televie Grant No. 7651819F.
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