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Anticancer drugs

Finding the perfect combination

Nature Reviews Drug Discovery volume 14, page 13 (2015)Cite this article

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The study focused on non-small-cell lung cancers (NSCLCs) that harbour activating mutations in EGFR or ALK, which are routinely treated with specific tyrosine kinase inhibitors (TKIs). Resistance usually develops within 1–2 years, through a variety of mechanisms — for example, mutations can prevent target inhibition by the TKI ('gatekeeper' mutations) or activate compensatory signalling pathways ('bypass track' mutations). Cells that have developed bypass track resistance are insensitive to drugs targeted at either the driver oncogene or the components of the compensatory signalling pathway; however, they are sensitive to a combination of these drugs.

To examine mechanisms of resistance and identify effective drugs, the authors generated cell lines directly from tumour biopsies — a process facilitated by recent advances in cell culture methods. The cells were then subjected to a screen that combined the original TKI (against which cells had become resistant) with a panel of 76 drugs targeted at key regulators of cell proliferation and survival. Proof-of-principle was generated using five cell lines for which the mechanisms of resistance were known; the screen successfully identified the inhibitors of the known compensatory signalling pathways. The system was then tested in 55 NSCLC cell lines that had acquired resistance of unknown mechanism. 20 of these cell lines were directly derived from patients who had progressed on ALK or EGFR inhibitors, and the remaining cell lines were generated in vitro.

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References

  1. Crystal, A. S. et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science http://dx.doi.org/10.1126/science.1254721 (2014)

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Authors
  1. Alexandra Flemming
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Flemming, A. Finding the perfect combination. Nat Rev Drug Discov 14, 13 (2015). https://doi.org/10.1038/nrd4524

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