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Therapeutics

Delving deeper into resistance

Nature Reviews Cancer volume 14, page 7 (2014)Cite this article

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Johannessen et al. conducted a screen for genes that induced resistance to inhibitors targeting RAF, MEK or ERK, or RAF and MEK combined in a BRAF-V600E melanoma cell line. Many of the hits were involved in G protein-coupled receptor (GPCR) signalling. GPCRs induce production of cyclic AMP (cAMP) from ATP by adenyl cyclase, and cAMP activates protein kinase A (PKA). Both cAMP and an adenyl cyclase activator (forskolin) induced PKA-dependent resistance to ERK pathway inhibitors. Downstream of PKA, the transcription factor cAMP response element-binding protein (CREB) was also required for ERK pathway inhibitor resistance. CREB activation was high in pretreatment biopsy samples from patients with BRAF-V600E melanoma, was suppressed during RAF inhibitor therapy and then increased to pretreatment levels following relapse. One of the genes activated by CREB in cell lines was microphthalmia-associated transcription factor (MITF), a lineage-survival oncogene in melanoma, and MITF knockdown blocked ERK pathway inhibitor resistance mediated by forskolin. Finally, histone deacetylase (HDAC) inhibitors can reduce MITF expression, and, although HDAC inhibitors have other effects, they reversed forskolin-mediated resistance to ERK pathway inhibitors.

highlighting the heterogeneous nature of RAF inhibitor resistance

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References

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  1. Sarah Seton-Rogers
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Seton-Rogers, S. Delving deeper into resistance. Nat Rev Cancer 14, 7 (2014). https://doi.org/10.1038/nrc3653

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