Abstract P5-05-04: A novel inhibitor of cancer stem cells overcomes chemotherapy resistance of triple negative breast cancers
Authors: Katsutoshi Sato, Amol Padgaonkar, Stephen Cosenza, Stacey Baker, Ramana Reddy, E Premkumar Reddy, Hanna Y. Irie
Journal: Cancer Research (2020)

Abstract Background/Rationale: Sensitivity to chemotherapy is a strong, consistent predictor of survival for patients diagnosed with triple negative breast cancer (TNBC) and chemotherapy resistance remains a critical problem for a subset of patients. Cancer cells with a stem cell-like profile are thought to represent a relatively chemotherapy resistant subpopulation. A screen for novel inhibitors of these cancer stem cell-like cells identified the multi-kinase inhibitor ON108600 that inhibits Casein kinase 2 (CK2), TNIK and Dyrk kinases. We sought to determine whether treatment with ON108600 enhances chemotherapy sensitivity of aggressive, multi-drug resistant TNBC, thereby offering a novel therapeutic option for patients with high risk TNBC. Methods: Patient-derived xenograft (PDX) models derived from patients with chemotherapy-resistant primary or metastatic TNBC were screened for expression of ON108600 targets prior to selection for in vivo studies. Studies to confirm target engagement in vivo were performed to optimize dosing schedules. Selected PDX models were expanded and treated with vehicle control, ON108600, Paclitaxel, or ON108600/Paclitaxel combination. Tumor growth was assessed. Tumors were harvested at end point for histological analysis. Results: Chemotherapy- resistant TNBC PDX models were screened for protein expression of CK2, Dyrk and TNIK kinases. Two models with the highest level of these kinases were selected and propagated for in vivo studies; one model is derived from a primary TNBC with intrinsic resistance to chemotherapy while the second is derived from a heavily pre-treated metastatic TNBC. Target engagement was confirmed by assessing levels of CK2 substrates in tumors treated with different doses of ON108600. Expanded cohorts of these PDX models were treated with ON108600, Paclitaxel or combined ON108600/Paclitaxel. While Paclitaxel chemotherapy had minimal effect on tumor growth in these PDX models, combined ON108600/Paclitaxel treatment significantly suppressed growth and/or caused regression of these aggressive tumors. Importantly, combination treatment was associated with minimal toxicity. RNASeq profiling of PDX tumors treated with ON108600 or vehicle control was performed, revealing suppression of multiple oncogenic pathways by ON108600 which are currently being validated. Conclusions: ON108600, identified as an inhibitor of a cancer stem cell-like population, overcomes Paclitaxel resistance to suppress growth of aggressive TNBC for which treatment options remain limited. These results support further study and clinical translation of ON108600. Citation Format: Katsutoshi Sato, Amol Padgaonkar, Stephen Cosenza, Stacey Baker, Ramana Reddy, E Premkumar Reddy, Hanna Y. Irie. A novel inhibitor of cancer stem cells overcomes chemotherapy resistance of triple negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-04.