SRC Inhibition Overcomes Trastuzumab Resistance in HER2-Overexpressing Breast Cancers

Overexpression of human epidermal growth factor receptor-2 (HER2 or ERBB2) is associated with poor clinical prognosis and survival in breast cancer. Treatment with trastuzumab, a humanized antibody that targets HER2, in patients with HER2-positive breast cancer shows clinical benefit; however, many patients do not respond to treatment due to either de novo or acquired resistance. Because of the heterogeneity of trastuzumab resistance, management of patients with HER2-positive breast cancer remains clinically challenging. In a recent article, Zhang and colleagues identify activation of the nonreceptor tyrosine kinase SRC to be the key node common to both the de novo and acquired mechanisms of trastuzumab resistance. Using trastuzumab-resistant, HER2-overexpressing breast cancer cells, the authors first show that SRC activation, mediated by increased phosphorylation at Tyr416, occurs downstream of multiple receptor tyrosine kinase pathways and plays a critical role in acquired trastuzumab resistance. SRC is also shown to interact directly with the protein phosphatase PTEN, and PTEN loss in breast cancer cells results in SRC phosphorylation and development of de novo trastuzumab resistance. Importantly, in both in vitro and in vivo models, treatment with saracatinib, an orally available small molecule inhibitor of SRC, sensitized trastuzumab-resistant cells and tumors to trastuzumab treatment. A retrospective analysis of primary breast tumors further correlated relative increases in SRC activity with clinical resistance to trastuzumab. Overall, the results suggest that combined treatment with both trastuzumab and SRC inhibitor can overcome resistance and provide more effective therapy for patients with HER2-overexpressing breast cancer.

Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 2011;17:461–9.

Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.