Trastuzumab (Herceptin) has greatly improved survival odds for women with HER2-positive breast cancer, but treatment resistance remains a problem for at least 50% of patients. A new study by a team of researchers with University of Texas MD Anderson Cancer Center indicates that the novel agent saracatinib might offer a solution. Saracatinib inhibits SRC, a proto-oncogene.
Building on earlier research that connected loss of the PTEN tumor suppressor gene with trastuzumab resistance, Siyuan Zhang, PhD, lead author of the study, and colleagues found that PTEN targets SRC and that SRC activity correlates with tumor response. In vitro studies with human breast cell lines showed that >90% of HER2-positive tumors with low levels of SRC expression responded to trastuzumab compared with 40% of tumors demonstrating high SRC expression.
In mouse models of human breast cancer, 3 weeks of treatment with trastuzumab shrank tumors with low levels of SRC down to 20% of their starting volume, while tumors expressing high levels of SRC grew by nearly 400%. Additional research found that breast cancer patients demonstrating little SRC activity survived a median of 57.9 months compared with 34.2 months for patients with high levels of SRC.
Zhang said these and other experiments led to the team’s decision to pair saracatinib with trastuzumab and test it in HER2-positive breast cancer. Mice with trastuzumab-resistant breast tumors were treated with trastuzumab alone, saracatinib alone, or the drugs combined. Results were compared against results from a control group of untreated mice. After 25 days, tumors in mice given the combination regimen shrank by 90%. Tumors showed little change when treated only with trastuzumab. In the control group and in mice given saracatinib only, tumors grew by >200%. The combination of trastuzumab and saracatinib proved even more effective in a subgroup of mice with PTEN loss, reducing tumor volume by >90%.
In a press release, Dihua Yu, MD, PhD, a professor in the department of Molecular and Cellular Oncology at MD Anderson, said tumors have several means of resisting trastuzumab and taking 6 to 10 drugs to target every pathway of resistance would produce terrible side effects. SRC is a downstream target for multiple pathways associated with trastuzumab resistance, including IGF-1R, EGFR, ERBB2, HER3, and Met, which makes saracatinib a promising option.
Zhang noted that while dasatinib (Sprycel), approved by the FDA to treat chronic myeloid leukemia, also inhibits the SRC family of kinases, phase I and phase II clinical trials with saracatinib suggest that it has a more favorable side effects profile than dasatinib. The investigators are ready to evaluate saracatinib with trastuzumab in clinical trials.
Zhang S, Huang WC, Li P, et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nature Medicine. 2011. [Epub ahead of print.]