The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma
Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant ther...
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MDPI AG
2019-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/8/1093 |
| _version_ | 1797711490010054656 |
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| author | Mohammad Krayem Malak Sabbah Ahmad Najem An Wouters Filip Lardon Stephane Simon François Sales Fabrice Journe Ahmad Awada Ghanem E. Ghanem Dirk Van Gestel |
| author_facet | Mohammad Krayem Malak Sabbah Ahmad Najem An Wouters Filip Lardon Stephane Simon François Sales Fabrice Journe Ahmad Awada Ghanem E. Ghanem Dirk Van Gestel |
| author_sort | Mohammad Krayem |
| collection | DOAJ |
| description | Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1<sup>Met</sup>) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1<sup>Met</sup> caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration. |
| first_indexed | 2024-03-12T07:06:54Z |
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| language | English |
| last_indexed | 2024-03-12T07:06:54Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-26b780bd564a44c3a1634908fefd11cd2023-09-02T23:20:08ZengMDPI AGCancers2072-66942019-08-01118109310.3390/cancers11081093cancers11081093The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in MelanomaMohammad Krayem0Malak Sabbah1Ahmad Najem2An Wouters3Filip Lardon4Stephane Simon5François Sales6Fabrice Journe7Ahmad Awada8Ghanem E. Ghanem9Dirk Van Gestel10Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumCenter for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, BelgiumCenter for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, BelgiumDepartment of Radiation Oncology, Institut Jules Bordet, Université libre de Bruxelles, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumLaboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000 Brussels, BelgiumDepartment of Radiation Oncology, Institut Jules Bordet, Université libre de Bruxelles, 1000 Brussels, BelgiumRadiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1<sup>Met</sup>) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1<sup>Met</sup> caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration.https://www.mdpi.com/2072-6694/11/8/1093radiotherapy<sup>V600E</sup>BRAF inhibitionp53 activationintrinsic and acquired resistancemelanoma |
| spellingShingle | Mohammad Krayem Malak Sabbah Ahmad Najem An Wouters Filip Lardon Stephane Simon François Sales Fabrice Journe Ahmad Awada Ghanem E. Ghanem Dirk Van Gestel The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma Cancers radiotherapy <sup>V600E</sup>BRAF inhibition p53 activation intrinsic and acquired resistance melanoma |
| title | The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma |
| title_full | The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma |
| title_fullStr | The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma |
| title_full_unstemmed | The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma |
| title_short | The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma |
| title_sort | benefit of reactivating p53 under mapk inhibition on the efficacy of radiotherapy in melanoma |
| topic | radiotherapy <sup>V600E</sup>BRAF inhibition p53 activation intrinsic and acquired resistance melanoma |
| url | https://www.mdpi.com/2072-6694/11/8/1093 |
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