The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma
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 r...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-05-01
|
| Series: | Frontiers in Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2023.1149918/full |
| _version_ | 1797833621704278016 |
|---|---|
| author | Malak Sabbah Ahmad Najem Christophe Vanderkerkhove Fabien Kert Younes Jourani Fabrice Journe Ahmad Awada Dirk Van Gestel Ghanem E. Ghanem Mohammad Krayem Mohammad Krayem |
| author_facet | Malak Sabbah Ahmad Najem Christophe Vanderkerkhove Fabien Kert Younes Jourani Fabrice Journe Ahmad Awada Dirk Van Gestel Ghanem E. Ghanem Mohammad Krayem Mohammad Krayem |
| author_sort | Malak Sabbah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:26:04Z |
| format | Article |
| id | doaj.art-6af0efc13c724c449444df05984206e0 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-04-09T14:26:04Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-6af0efc13c724c449444df05984206e02023-05-04T04:15:56ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-05-011010.3389/fmed.2023.11499181149918The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanomaMalak Sabbah0Ahmad Najem1Christophe Vanderkerkhove2Fabien Kert3Younes Jourani4Fabrice Journe5Ahmad Awada6Dirk Van Gestel7Ghanem E. Ghanem8Mohammad Krayem9Mohammad Krayem10Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, BelgiumLaboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, BelgiumMedical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumMedical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumMedical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumLaboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, BelgiumOncology Medicine Department, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumRadiation Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumLaboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, BelgiumLaboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Bruxelles, BelgiumRadiation Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Brussels, BelgiumMelanoma 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.https://www.frontiersin.org/articles/10.3389/fmed.2023.1149918/fullmelanomaradiotherapyWTBRAFRTK inhibitionPARP inhibition |
| spellingShingle | Malak Sabbah Ahmad Najem Christophe Vanderkerkhove Fabien Kert Younes Jourani Fabrice Journe Ahmad Awada Dirk Van Gestel Ghanem E. Ghanem Mohammad Krayem Mohammad Krayem The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma Frontiers in Medicine melanoma radiotherapy WTBRAF RTK inhibition PARP inhibition |
| title | The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma |
| title_full | The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma |
| title_fullStr | The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma |
| title_full_unstemmed | The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma |
| title_short | The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma |
| title_sort | benefit of co targeting parp 1 and c met on the efficacy of radiotherapy in wild type braf melanoma |
| topic | melanoma radiotherapy WTBRAF RTK inhibition PARP inhibition |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2023.1149918/full |
| work_keys_str_mv | AT malaksabbah thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ahmadnajem thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT christophevanderkerkhove thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT fabienkert thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT younesjourani thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT fabricejourne thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ahmadawada thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT dirkvangestel thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ghanemeghanem thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT mohammadkrayem thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT mohammadkrayem thebenefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT malaksabbah benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ahmadnajem benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT christophevanderkerkhove benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT fabienkert benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT younesjourani benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT fabricejourne benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ahmadawada benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT dirkvangestel benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT ghanemeghanem benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT mohammadkrayem benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma AT mohammadkrayem benefitofcotargetingparp1andcmetontheefficacyofradiotherapyinwildtypebrafmelanoma |