Abstract A15: Dual inhibition of the PI3K-mTOR signaling in combination with HER2 inhibitor is necessary for maximal antitumor activity in HER2+ breast cancer cells

Abstract

Abstract Background: Despite huge success in the treatment of HER2 amplified/overexpressed breast cancers, resistance is challenging problem even to combinations of HER2 targeting inhibitors. Multiple mechanisms of resistance have been studied and the PI3K-mTOR pathway inhibition is critical for the efficacy of HER2 inhibitors. Activating mutations in PIK3CA can overlap with HER2 overexpression and have been shown to confer resistance to HER2 inhibitors including trastuzumab (T) in preclinical studies. Methods: HER2+/T-sensitive/PIK3CA wild type (BT474) and HER2+/PIK3CA mutated (HCC1954) cells were used for this study. The impact of PIK3CA mutation on the effect of HER2 and dual PI3K/mTOR inhibitors was assayed by immunoblot, proliferation and apoptosis assays. PI3K signaling was examined by immunoblot for phosphoproteins in the HER2-PI3K-mTOR signaling cascade. The combination of dual PI3K/mTOR inhibitor (GDC-0980) with HER2 antibodies (T or T-DM1) was studied in HER2 amplified models with wild type or mutant PIK3CA. Results: Our data showed that 1) PIK3CA mutation in HER2+ cells was responsible for resistance to the HER2-specific antibody trastuzumab, 2) T-resistance conferred by this activating PIK3CA mutation was overcome by blockade of the PI3K-mTOR pathway with GDC-0980, 3) T-DM1 and GDC-0980 combination treatment greatly induced apoptosis of both BT474 and HCC1954 cells as indicated by Annexin V staining, 4) in mice bearing HER2+/T-sensitive/PIK3CA wild type xenografts (BT474), T or T-DM1 blocked tumor growth. The addition of a dual PI3K/mTOR inhibitor more significantly blocked tumor growth when compared to control group, 5) in a HER2+/PIK3CA mutant xenograft (HCC1954), dual PI3K/mTOR inhibition with GDC-0980 in combination with T or T-DM1 was required for blocked of tumor growth and tumor regression, and 6) immununo-staining of tumors from GDC-0980 treated mice showed growth inhibition (Ki67), and a decreased in associated angiogenesis (CD31). Conclusion: These results suggest that the combination of GDC-0980 may be a potential strategy for the treatment of trastzumab-resistant breast cancer mediated by activating mutation of PIK3CA and this combination also provides benefit to HER2+/PIK3CA wild type tumors. Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Dual inhibition of the PI3K-mTOR signaling in combination with HER2 inhibitor is necessary for maximal antitumor activity in HER2+ breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A15.