Novel inhibitor of breast cancer stem cells overcomes chemotherapy resistant triple negative breast cancer

Katsutoshi Sato, Amol A Padgaonkar, Stacey J. Baker, Stephen C. Cosenza, Olga Rechkoblit, DRC Venkata Subbaiah, Josep Domingo-Domenech, Alison Bartkowski, Elisa R. Port, Aneel K. Aggarwal, M.V. Ramana Reddy, Hanna Y. Irie, and E. Premkumar Reddy
Published in Cancer
Novel inhibitor of breast cancer stem cells overcomes chemotherapy resistant triple negative breast cancer
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Approximately 10 - 15 % of diagnosed breast cancers are triple negative breast cancer (TNBC) (1, 2). Although TNBC is treated with standard chemotherapeutic drugs such as paclitaxel, the response is variable, and many patients still recur with metastatic disease that is often fatal (3, 4). Many TNBCs are clearly resistant to current therapeutic regimens. One driving factor behind chemoresistance and tumor aggressiveness of TNBC is breast cancer stem cells (BCSC). BCSCs have the ability to self-renew and represent a relatively quiescent subpopulation of tumor cells that can escape the effects of chemotherapy because of their slower rate of proliferation, expression of drug transporters that can expel chemotherapeutics and higher DNA repair potential (5, 6). BCSCs are identified as the CD44high/CD24low or ALDHhigh subpopulation, and existence of the cells with these hallmarks correlates with poor prognosis of TNBC patients (7). Therefore, targeted inhibition of BCSC could enhance the efficacy of chemotherapy and improve outcomes for patients diagnosed with aggressive TNBC.

In this study, we functionally screened 4000 compounds for ability to inhibit and kill BCSC and discovered 108600. In vitro kinase profiling showed that the targets of 108600 are CK2 (Casein Kinase 2) DYRK1 (dual specificity tyrosine phosphorylation regulated kinase) and TNIK (TNF receptor associated factor 2 and NCK interacting kinase). CK2 interacts with AKT1 and Cyclin D1, and regulates cell cycle progression, apoptosis, energy metabolism, and DNA repair (8). DYRK1 is a regulator of quiescence, keeping cells in the G0/G1 phase (10) TNIK is an important regulator of WNT/β-catenin pathway; its interaction with TCF/LEF strongly promotes transcription of β-catenin target genes, such as c-MYC, Cyclin D1, and AXIN2 (11).

Although all three kinases have been reported to play a role in stem cell maintenance, there have been no previous simultaneous inhibitor. One of the key advantages of 108600 is its ability to suppress simultaneously and rather selectively, multiple pathways that promote survival of CSCs, avoiding the problem of redundant, compensatory signaling that compromised previous approaches.

In our studies, 108600 suppresses growth of patient-derived xenograft (PDX) tumor grafts derived from patient cancers that responded poorly to standard chemotherapy like paclitaxel. 108600 as a single agent or in synergistic combination with chemotherapy dramatically inhibited growth of these chemotherapy resistant tumors by decreasing the ALDHhigh subpopulation within these tumors. This was consistent with our hypothesis that inhibiting CSCs sensitizes cancers to chemotherapy. As we aim to move toward clinical translation to early phase trials, we tested the efficacy of 108600 against established TNBC metastases in mouse models, a scenario that simulates stage 4 TNBC disease in patients. Remarkably, combined 108600 and paclitaxel nearly completely eliminated metastases, supporting the promising potential of 108600 as an effective therapy for patients with advanced disease.

In addition to chemotherapy resistance, CSCs have also been associated with immune evasion. BCSCs could play a role in regulating the immune response to TNBC and could compromise the efficacy of immunotherapies that are increasingly used in the treatment of TNBC. Therefore, targeting BCSCs with 108600 could offer a novel strategy to enhance the efficacy of immunotherapeutics and we are actively pursuing these studies to evaluate its clinical potential.

A. 108600 inhibited kinase function of CK2α1, CK2α2, DYRK1A, DYRK1B, DYRK2, and TNIK at nanomolar concentrations. B. 108600 alone suppressed both of tumor growth and spontaneous lung metastasis of Luciferase labeled LM2-4 cells engrafted on NSG mice. Combination with paclitaxel synergistically eliminated the metastasis.

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