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Anticancer drugs

SRC hits the mark

Nature Reviews Drug Discovery volume 10, pages 338–339 (2011)Cite this article

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Dihua Yu and colleagues analysed trastuzumab resistance in various ERBB2-overexpressing breast cancer cell lines and, as expected, resistance mechanisms were heterogeneous. After long-term exposure to trastuzumab, different cell lines acquired a range of RTK signalling alterations, including downregulation of ERBB2 and hyperactivation of epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R) or ERBB3. Additionally, loss of PTEN function, as occurs in a subset of ERBB2-overexpressing breast cancers (and the cell line MDA-MB-468), resulted in de novo trastuzumab resistance.

Despite the heterogeneity of these resistance mechanisms, a comparison of signalling between sensitive and resistant cell line pairs revealed that hyperactivation of SRC (as shown by SRC Tyr416 phosphorylation) in resistant cells was surprisingly universal. Interestingly, the authors demonstrated that the Tyr416 phosphate of activated SRC is a direct substrate for the PTEN phosphatase, explaining how loss of PTEN can result in SRC activation.

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ORIGINAL RESEARCH PAPER

  1. Zhang, S. et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nature Med. 13 Mar 2011 (doi:10.1038/nm.2309)

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Authors
  1. Darren J. Burgess
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This article is modified from the original in Nature Rev. Cancer (doi:10.1038/nr3062).

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Burgess, D. SRC hits the mark. Nat Rev Drug Discov 10, 338–339 (2011). https://doi.org/10.1038/nrd3451

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