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FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma

Abstract : 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.
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https://www.hal.inserm.fr/inserm-03033439
Contributor : Nicolas Dumaz Connect in order to contact the contributor
Submitted on : Tuesday, December 1, 2020 - 1:11:57 PM
Last modification on : Wednesday, December 1, 2021 - 1:40:02 PM
Long-term archiving on: : Tuesday, March 2, 2021 - 7:15:30 PM

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Pauline Tétu, Julie Delyon, Jocelyne André, Coralie Reger de Moura, Malak Sabbah, et al.. FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma. Cancers, MDPI, 2020, 12 (5), pp.1062. ⟨10.3390/cancers12051062⟩. ⟨inserm-03033439⟩

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