A Functional Landscape of Resistance to MEK1/2 and CDK4/6 Inhibition in NRAS-Mutant Melanoma

Cancer Research
Tikvah K HayesCory Johannessen

Abstract

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then used a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PI3K signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6, or their combination in NRAS-mutant melanoma. SIGNIFICANCE: These findings reveal that NRAS-...Continue Reading

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Citations

Aug 14, 2019·Pigment Cell & Melanoma Research·Elisa BertoliAlessandro Marco Minisini
Apr 15, 2020·Cancer Cell·Mónica Álvarez-Fernández, Marcos Malumbres
May 1, 2021·International Journal of Molecular Sciences·Diana Valentina TudorGabriela Adriana Filip
Jun 3, 2021·Cells·Mattia GaruttiFabio Puglisi
Jun 8, 2021·Cancer Treatment Reviews·Tijana RandicStephanie Kreis
Jun 10, 2021·Expert Reviews in Molecular Medicine·Marika A V Reinius, Elizabeth Smyth
Jun 15, 2021·Frontiers in Oncology·Cristian ScatenaSara Tomei

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