FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma
KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performe...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/5/1062 |
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| author | Pauline Tétu Julie Delyon Jocelyne André Coralie Reger de Moura Malak Sabbah Ghanem E Ghanem Maxime Battistella Samia Mourah Céleste Lebbé Nicolas Dumaz |
| author_facet | Pauline Tétu Julie Delyon Jocelyne André Coralie Reger de Moura Malak Sabbah Ghanem E Ghanem Maxime Battistella Samia Mourah Céleste Lebbé Nicolas Dumaz |
| author_sort | Pauline Tétu |
| collection | DOAJ |
| description | KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma. |
| first_indexed | 2024-03-10T20:14:26Z |
| format | Article |
| id | doaj.art-5bd985c089ae4443aeeec7255d17093a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:14:26Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5bd985c089ae4443aeeec7255d17093a2023-11-19T22:41:15ZengMDPI AGCancers2072-66942020-04-01125106210.3390/cancers12051062FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated MelanomaPauline Tétu0Julie Delyon1Jocelyne André2Coralie Reger de Moura3Malak Sabbah4Ghanem E Ghanem5Maxime Battistella6Samia Mourah7Céleste Lebbé8Nicolas Dumaz9INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceLaboratory 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, BelgiumINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceINSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, FranceKIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma.https://www.mdpi.com/2072-6694/12/5/1062melanomatargeted therapy resistanceKITMAPKFGF2 BIM |
| spellingShingle | Pauline Tétu Julie Delyon Jocelyne André Coralie Reger de Moura Malak Sabbah Ghanem E Ghanem Maxime Battistella Samia Mourah Céleste Lebbé Nicolas Dumaz FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma Cancers melanoma targeted therapy resistance KIT MAPK FGF2 BIM |
| title | FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma |
| title_full | FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma |
| title_fullStr | FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma |
| title_full_unstemmed | FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma |
| title_short | FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma |
| title_sort | fgf2 induces resistance to nilotinib through mapk pathway activation in kit mutated melanoma |
| topic | melanoma targeted therapy resistance KIT MAPK FGF2 BIM |
| url | https://www.mdpi.com/2072-6694/12/5/1062 |
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