SIRT6 haploinsufficiency linked to melanoma-treatment resistance


By Reuters Staff

NEW YORK (Reuters Health) - Haploinsufficiency of the histone deacetylase SIRT6 allows persistence of melanoma cells in the presence of therapeutic MAPK signaling inhibitors (MAPKi), researchers report.

Patients with advanced metastatic melanoma harboring certain BRAF mutations (BRAF-V600E/K) respond to treatment with MAPKi, but subsequent resistance is a major clinical challenge. Genetic mutations account for only a fraction of acquired resistance cases, and epigenetic mechanisms of melanoma drug resistance remain poorly understood.

Dr. Emily Bernstein from Icahn School of Medicine at Mount Sinai, in New York City, and colleagues performed a CRISPR-Cas9 screen in human melanoma cells, targeting chromatin modifiers in the context of MAPKi. They identified SIRT6 as a regulator of resistance to the BRAF inhibitor dabrafenib or to the combination of dabrafenib and trametinib (a MEK inhibitor) in BRAF-V600E melanoma.

Haploinsufficiency of SIRT6 in these melanoma cells significantly decreased their sensitivity to MAPKi through the activation of IGF-1R/AKT signaling and subsequent increases in IGFBP2 expression, the researchers report in Nature Communications, online August 24.

In contrast, complete loss of SIRT6 did not promote IGFBP2 expression, but rather allowed sensitivity to MAPKi through a DNA damage response.

Inhibition of IGF-1R signaling using linsitinib, combined with dabrafenib, significantly reduced melanoma cell proliferation and led to increased apoptosis, compared with treatment with either agent alone.

These findings reveal "a previously unknown epigenetic mechanism of melanoma drug resistance, a dose-dependent effect of SIRT6 levels on the drug resistance phenotype, and a combinatorial therapy that may overcome resistance to MAPKi for a subset of BRAF-V600-mutant melanoma patients," the researchers conclude.

Dr. Bernstein was unable to provide comments in time for publication.


Nat Commun 2018.

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