The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma Article Swipe
Mohammad Krayem
,
Malak Sabbah
,
Ahmad Najem
,
An Wouters
,
Filip Lardon
,
Stéphane Simon
,
François Salès
,
Fabrice Journé
,
Ahmad Awada
,
Ghanem Ghanem
,
Dirk Van Gestel
·
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.3390/cancers11081093
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.3390/cancers11081093
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-1Met) 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-1Met 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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3390/cancers11081093
- https://www.mdpi.com/2072-6694/11/8/1093/pdf?version=1564656832
- OA Status
- gold
- Cited By
- 24
- References
- 77
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2966715002
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2966715002Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3390/cancers11081093Digital Object Identifier
- Title
-
The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in MelanomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2019Year of publication
- Publication date
-
2019-08-01Full publication date if available
- Authors
-
Mohammad Krayem, Malak Sabbah, Ahmad Najem, An Wouters, Filip Lardon, Stéphane Simon, François Salès, Fabrice Journé, Ahmad Awada, Ghanem Ghanem, Dirk Van GestelList of authors in order
- Landing page
-
https://doi.org/10.3390/cancers11081093Publisher landing page
- PDF URL
-
https://www.mdpi.com/2072-6694/11/8/1093/pdf?version=1564656832Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.mdpi.com/2072-6694/11/8/1093/pdf?version=1564656832Direct OA link when available
- Concepts
-
Radioresistance, Vemurafenib, Melanoma, Cancer research, MAPK/ERK pathway, Radiosensitivity, Radiation therapy, Medicine, Dacarbazine, Protein kinase B, PI3K/AKT/mTOR pathway, Kinase, Phosphorylation, Internal medicine, Biology, Signal transduction, Metastatic melanoma, Cell biologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
24Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2, 2023: 5, 2022: 5, 2021: 4, 2020: 5Per-year citation counts (last 5 years)
- References (count)
-
77Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2156078931, https://openalex.org/W4211223138, https://openalex.org/W2174981182, https://openalex.org/W2915425920, https://openalex.org/W2497822529, https://openalex.org/W2165320653, https://openalex.org/W6721010770, https://openalex.org/W2126194543, https://openalex.org/W2130186240, https://openalex.org/W2066068067, https://openalex.org/W2790093035, https://openalex.org/W2581294190, https://openalex.org/W4211008944, https://openalex.org/W2223833389, https://openalex.org/W2922307209, https://openalex.org/W2912115437, https://openalex.org/W2163188200, https://openalex.org/W1968530572, https://openalex.org/W2009228205, https://openalex.org/W2887691759, https://openalex.org/W1985928174, https://openalex.org/W2082330503, https://openalex.org/W2565830824, https://openalex.org/W1636392194, https://openalex.org/W2781521480, https://openalex.org/W1992029253, https://openalex.org/W2028282498, https://openalex.org/W2080772875, https://openalex.org/W2077372900, https://openalex.org/W1968300343, https://openalex.org/W2057004636, https://openalex.org/W2046585589, https://openalex.org/W2168302736, https://openalex.org/W2027203760, https://openalex.org/W2138244274, https://openalex.org/W2258872553, https://openalex.org/W2035294512, https://openalex.org/W2127713467, https://openalex.org/W2776139938, https://openalex.org/W2528832773, https://openalex.org/W2805484370, https://openalex.org/W2142765738, https://openalex.org/W2737216197, https://openalex.org/W2026197139, https://openalex.org/W2146629016, https://openalex.org/W2023676537, https://openalex.org/W2091951306, https://openalex.org/W2133739473, https://openalex.org/W2519798719, https://openalex.org/W2099356406, https://openalex.org/W1215179222, https://openalex.org/W184760362, https://openalex.org/W2025798292, https://openalex.org/W2068596197, https://openalex.org/W6748758890, https://openalex.org/W2132834292, https://openalex.org/W2093629917, https://openalex.org/W2009152256, https://openalex.org/W1969951885, https://openalex.org/W2740775105, https://openalex.org/W2040881358, https://openalex.org/W2153172903, https://openalex.org/W2062088207, https://openalex.org/W2482655950, https://openalex.org/W2067311782, https://openalex.org/W2792065646, https://openalex.org/W2472987080, https://openalex.org/W2924943159, https://openalex.org/W2109146058, https://openalex.org/W2102684430, https://openalex.org/W2067751798, https://openalex.org/W2128260490, https://openalex.org/W2070317104, https://openalex.org/W2810672264, https://openalex.org/W2790945713, https://openalex.org/W1975721268, https://openalex.org/W2767133684 |
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