科研之友
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摘要
Dysregulated expression and/or mutations of the various components of the phosphoinositide 3-kinase (PI3K)/Akt pathway occur with high frequency in prostate cancer and are associated with the development and progression of castration resistant tumors. However, small molecule kinase inhibitors that target this signaling pathway have limited efficacy in inhibiting tumor growth, primarily due to compensatory survival signals through receptor tyrosine kinases (RTKs). Although members of the epidermal growth factor receptor (EGFR), or HER, family of RTKs are strongly implicated in the development and progression of prostate cancer, targeting individual members of this family such as EGFR or HER2 has resulted in limited success in clinical trials. Multiple studies indicate a critical role for HER3 in the development of resistance against both HER-targeted therapies and PI3K/Akt pathway inhibitors. In this study, we found that the growth inhibitory effect of GDC-0941, a class I PI3K inhibitor, is markedly reduced in the presence of heregulin. Interestingly, this effect is more pronounced in cells lacking phosphatase and tensin homolog function. Heregulin-mediated resistance to GDC-0941 is associated with reactivation of Akt downstream of HER3 phosphorylation. Importantly, combined blockade of HER2 and HER3 signaling by an anti-HER2/HER3 bispecific antibody or a mixture of anti-HER2 and anti-HER3 antibodies restores sensitivity to GDC-0941 in heregulin-treated androgen-dependent and -independent prostate cancer cells. These studies indicate that the combination of PI3K inhibitors with HER2/HER3 targeting antibodies may constitute a promising therapeutic strategy for prostate cancer. What's new? Changes in the PI3K/Akt pathway often accompany prostate cancer. But attempts to halt the cancer by targeting this pathway are frustratingly ineffective, as they are thwarted by the HER family of kinases. This study showed that the HER3 ligand, heregulin, allows prostate cancer cells to fend off the PI3K inhibitor, GDC-0941. The authors then went on to demonstrate that they could reverse this effect; targeting HER2 and HER3 with antibodies allowed the inhibitor to again stop the growth of the cancer. Thus, antibodies to HER2 /HER3 may enhance the effectiveness of PI3K inhibitors to treat prostate cancer in patients.
- 出版日期2015-7-15
