Abstract P2-03-08: Preclinical evaluation of the PI3Kα/δ inhibitor, copanlisib in HER2+ breast cancer: A proof of concept study

Purpose: The PI3K-AKT-mTORC1/C2 pathway is frequently activated in HER2+ breast cancer and upregulation of this pathway is a key mechanism of trastuzumab resistance. However, attempts to indirectly target this pathway by using the allosteric mTOR inhibitor everolimus have had limited clinical success. Here, we present the results of a preclinical study of the PI3K α/δ (dominant) inhibitor copanlisib alone and in combination with T-DM1, in HER2 amplified cell lines including a model with acquired resistance to trastuzumab. Method: Anti-proliferative, apoptotic, cell cycle, and intracellular signaling effects of copanlisib alone and in combination with T-DM1 were evaluated in a panel of HER2 amplified (ER+ or ER-), and HER2 amplified/PIK3CA mutated cell lines, as well as trastuzumab-resistant breast cancer cell lines. Results: 1) Copanlisib inhibited PI3K, mTOR and their downstream signaling molecules in HER2 amplified/PIK3CA WT or PIK3CA mutated as well as in trastuzumab-resistant cell lines, 2) interestingly, copanlisib also inhibited RAS-MAPK signaling in the earlier time points, 3) copanlisib caused a strong differential growth inhibition in HER2 amplified BC cell lines by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom. Inhibition was greater when copanlisib was combined with T-DM1, 4) administration of copanlisib induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependent manner, 5) unlike everolimus copanlisib blocked HIF1α accumulation in hypoxic condition and this blocking effect was reversed by prior treatment with the proteasome inhibitor, carfilzomib and 6) copanlisib also attenuated HER2 amplified cell migration, an important phenotypic feature for metastasis. Conclusions: Copanlisib is highly effective (blocks proliferation, induces apoptosis, and inhibits PI3K and its downstream signaling targets) in HER2 amplified breast cancer cell lines including trastuzumab-resistant and PIK3CA mutated cell lines. The addition of copanlisib to T-DM1 might represent an improved treatment strategy for patients with refractory metastatic HER2+ breast cancer. Citation Format: De P, Carlson JH, Dey N, Leyland-Jones B. Preclinical evaluation of the PI3Kα/δ inhibitor, copanlisib in HER2+ breast cancer: A proof of concept study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-08.