Combination Therapy Of The Novel Pi3k Inhibitor Gdc-0941 And Dual Pi3k/Mtor Inhibitor Gdc-0980 With Trastuzumab-Dm1 Antibody Drug Conjugate Enhances Anti-Tumor Activity In Preclinical Breast Cancer Models In Vitro And In Vivo

The receptor tyrosine kinase, HER2/ErbB2, is a validated clinical target for HER2-amplified breast cancer, as evidenced by the U.S.F.D.A. approval of the humanized HER2 antibody, trastuzumab (Herceptin®), and the dual HER2/EGFR small molecule tyrosine kinase inhibitor lapatinib (Tykerb®). An alternative approach for targeting HER2 is the direct covalent coupling of a cytotoxic drug to trastuzumab. We have previously reported the potent in vitro and in vivo efficacy of T-DM1, trastuzumab (T) linked to the microtubule polymerization inhibitory drug maytansinoid (DM1), in trastuzumab-sensitive and-refractory breast tumor models (1). Inhibition of signaling through PI3K, which is hyperactivated in HER2-amplified breast cancer due to constitutive activity of overexpressed HER2 and/or through mutation of the p110-α subunit of PI3K, also offers an additional therapeutic approach. Therefore the specific aims of our study were to determine if the combination of a novel pan-PI3K inhibitor (GDC-0941) or a dual PI3K/mTOR inhibitor (GDC-0980) enhanced the anti-tumor activity of T-DM1 in HER2-amplified breast cancer lines in vitro and as xenografts in vivo. The breast cancer cell lines tested, MCF7 neo/HER2 and KPL4, harbor the E545K and H1047R PIK3CA mutations, respectively. Combination treatment of T-DM1 with either GDC-0941 or GDC-0980 in vitro resulted in a synergistic inhibition of cellular viability. Biochemical biomarker analyses revealed inhibition of phospho-Akt and phospho-ERK by both T-DM1 and GDC-0941, decreased phosphorylation of Rb and PRAS40 by GDC-0941, and increased levels of the mitotic markers phospho-histone H3 and cyclin B1 after treatment with T-DM1. In addition, T-DM1 treatment resulted in apoptosis as determined by appearance of the 23 kDa PARP-cleavage fragment, decreased levels of Bcl-XL, as well as activation of caspases 3 and 7. Addition of GDC-0941 to T-DM1 further enhanced apoptosis induction. In vivo, increased and sustained tumor regressions were observed when GDC-0941 was combined with T-DM1 as compared to single-agent activity in the MCF7 neo/HER2 and KPL4 sub-cutaneous xenograft models in a dose-dependent fashion. Moreover, an increased number of sustained complete regressions (CRs) were observed when GDC-0980 was combined with T-DM1 in the KPL4 xenograft model when compared to the combination treatment with GDC-0941 (% CRs = 88% for GDC-0980 + T-DM1 vs. 50% for GDC-0941 + T-DM1). The results of our pre-clinical studies provides evidence for the use of rational drug combinations of PI3K inhibitors such as GDC-0941 and GDC-0980 with T-DM1 in HER2-amplified breast cancer that harbor PIK3CA mutations and may offer additional treatment options for patients whose disease progresses on trastuzumab or lapatinib-based therapy. 1. Lewis Phillips, G. et al. Cancer Res 2008; 68: (22). Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-6.