Research ArticleCancer

A Network of Substrates of the E3 Ubiquitin Ligases MDM2 and HUWE1 Control Apoptosis Independently of p53

Sci. Signal.  07 May 2013:
Vol. 6, Issue 274, pp. ra32
DOI: 10.1126/scisignal.2003741

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Breaking Down to Build Resistance

Chemotherapeutic resistance often arises because of the rewiring of signaling pathways in cancer cells. Kurokawa et al. found that the ubiquitin E3 ligase MDM2 triggered the breakdown of another ubiquitin E3 ligase, HUWE1. In breast cancer cells that died when exposed to the HER2 (human epidermal growth factor receptor 2) EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor lapatinib, MDM2 was degraded, which enabled HUWE1 to trigger the degradation of a prosurvival protein and promote assembly and activation of a protein complex required for the execution of cell death. However, MDM2 degradation did not occur in lapatinib-resistant breast cancer cells, and thus, the abundance of HUWE1 was decreased, promoting cell survival. In a mouse xenograft model, an inhibitor of MDM2 reduced the growth of tumors generated from lapatinib-resistant breast cancer cells. Thus, MDM2 could be targeted to circumvent resistance to lapatinib in breast cancers.