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Targeted therapies

Understanding tumour drug addiction

Nature Reviews Cancer volume 17, pages 634–635 (2017)Cite this article

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Tumour cells with acquired resistance to targeted agents can develop a dependency on these drugs for survival, exposing potential therapeutic vulnerabilities. Kong et al. now provide insight into the previously uncharacterized mechanisms that underly 'drug addiction' in melanoma cells.

The authors next investigated whether transcriptional reprogramming mediated drug addiction. RNA profiling in drug-addicted cells after treatment cessation but before cell death revealed a major gene expression switch involving decreased expression of proliferation genes and elevated expression of cell invasion genes, suggesting a phenotypic switch reminiscent of epithelial-to-mesenchymal transition (EMT). Moreover, strong downregulation of microphthalmia-associated transcription factor (MITF) — a regulator of melanocyte cell lineage and EMT — and enrichment of AP-1, TEAD and JUNB transcriptional signatures were reported after drug discontinuation. Conversely, expression of JUNB, FRA1 and the receptor tyrosine kinase AXL was induced by drug withdrawal. Importantly, upregulation of fibronectin, downregulation of E-cadherin and enhanced migratory capacity in vitro — hallmarks of EMT — were observed following drug withdrawal.

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References

  1. Kong, X. et al. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature http://dx.doi.org/10.1038/nature24037 (2017)

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  1. Conor A. Bradley
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Bradley, C. Understanding tumour drug addiction. Nat Rev Cancer 17, 634–635 (2017). https://doi.org/10.1038/nrc.2017.98

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