Acquired resistance to BRAFi reverses senescence-like phenotype in mutant BRAF melanoma

Oncotarget
Mohammad KrayemGhanem Ghanem

Abstract

Targeting MAPK pathway in mutant BRAF melanoma with the specific BRAF inhibitor vemurafenib showed robust initial responses in the majority of patients followed by relapses due to acquired resistance to the drug. In V600EBRAF melanoma cell lines, senescence-associated β-galactosidase activity is often encountered in a constitutive manner or induced after MAPK inhibition. However, the link between the senescence-like phenotype and the resistance to BRAF inhibition is not fully understood yet. Our data validate a senescence-like phenotype (low cell proliferation, high cell volume, and high β-Gal activity) in mutant BRAF cells. Vemurafenib increased β-Gal activity in 4 out of 5 sensitive lines and in 2 out of 5 lines with intrinsic resistance to the drug. Interestingly, the 3 lines with acquired resistance to vemurafenib became depending on the drug for proliferation. In absence of drug, these lines showed a lower cell proliferation rate together with a substantial increase of β-Gal activity both in vitro and in vivo. In all settings, the senescence-like phenotype was significantly associated with an inhibition of pRB and cyclin D1, explaining the inhibition of cell proliferation. In conclusion, β-Gal activity is increased by V600...Continue Reading

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Citations

Jul 17, 2019·Pigment Cell & Melanoma Research·Ines Böhme, Anja Bosserhoff
Apr 3, 2020·International Journal of Oncology·Florencia Paula Madorsky RowdoJosé Mordoh
Apr 3, 2020·Cancers·Tareq SalehDavid A Gewirtz
Mar 10, 2020·Pigment Cell & Melanoma Research·Lucia González-RuizPablo Ramos-García

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Methods Mentioned

BETA
flow cytometry
xenograft
Protein Assay
PCR

Software Mentioned

ImmunoMembrane
AIDA ® Image Analyser
GraphPad Prism
ImmunoRatio
Image Reader

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