Abstract P5-10-07: A preclinical evaluation of the isoform-specific PI3K inhibitor in HER2+ breast cancer models with resistance to trastuzumab

Abstract

Abstract Background: The PI3K pathway mediates trastuzumab resistance. However, early attempts to indirectly target this signaling pathway with everolimus had limited success. We hypothesize that isoform-specific PI3K inhibitors may enhance the efficacy of anti-HER2 therapy. Methods: We conducted a preclinical proof-of-concept in vitro study of the selective PI3K alpha/delta inhibitor copanlisib or PI3K alpha inhibitor alpelisib alone and in combination with either trastuzumab (hmAB) or tucatinib (HER2-specific kinase inhibitor) in HER2 amplified breast cancer cell lines including trastuzumab-resistant (BT474HR), PIK3CA mutated/HER2 amplified (HCC1954 & MDA-MB453) and PIK3CA wild type/HER2 amplified (SKBR3). Results: When used alone or in combination with the HER2 targeted therapies trastuzumab or tucatinib, copanlisib and alpelisib have anti-proliferative effects in real-time cell proliferation or 3D-ON-TOP assays. Both isoform-specific inhibitors dose-dependently inhibited PI3K signaling and were effective regardless of trastuzumab-resistant and PIK3CA status. Compared to alpelisib, copanlisib was more effective in inducing apoptosis by Annexin V staining. Tucantinib dose-dependently blocked HER2 phosphorylation and p-HER2-SHC-GRB2-mediated MAPK signaling. Significantly, the combination of HER2-targeted therapy (trastuzumab or tucatinib) and copanlisib/alpelisib more effectively inhibited both 3D-ON-TOP colony formation and the HER2 downstream signaling cascade than either drug alone. Conclusion: Our study shows that blocking the PI3K pathway is an essential determinant of response to anti-HER2 regimens in trastuzumab-resistant breast cancers. Citation Format: Pradip De, Jennifer Carlson Aske, Nandini Dey. A preclinical evaluation of the isoform-specific PI3K inhibitor in HER2+ breast cancer models with resistance to trastuzumab [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-10-07.