Abstract 3010: Targeting metabolic pathways through pharmacological and chemotherapeutic interventions to improve triple-negative breast cancer therapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.3010-3010
• Main Authors: Ho, Alyssa N., Kiesel, Violet A., Connelly, Scott P., Coleman, Michael F., Hursting, Stephen D.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-3010

Triple-negative breast cancers (TNBCs) lack targeted therapies, leaving surgery and systemic chemotherapy as current standard approaches for treatment. However, chemotherapy resistance is a major clinical challenge. Stimulation of receptor tyrosine kinases such as insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) activates the protein kinase A (PKA), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling cascades. Activation of these pathways is observed in the majority of TNBC tumors and promotes pro-proliferative signaling. Thus IGF-1R/IR are potential therapeutic targets in TNBC, but clinical trials of anti-IGF-1R/IR therapies have consistently shown minimal and often heterogeneous therapeutic responses. Our objective was to determine whether metabolic reprogramming achieved by combination regimens, specifically the IGF-1R/IR inhibitor BMS-754807 and/or treatment with the platinum-based chemotherapeutic agent, carboplatin, promotes autophagy induction and sensitizes cancer cells to autophagy inhibition. Cytotoxicity of BMS-754807, alone or in combination with carboplatin and/or the autophagy inhibitor, hydroxychloroquine, was assessed in murine (E0771, metM-Wntlung, B6C3TAg 2.51) and human (MDA-MB-231, MDA-MB-468) models of TNBC using MTT assays. Analysis of mitochondrial mass was measured in cells stained with MitoTracker Green FM using flow cytometry. Autophagic flux was measured with an mCherry-EGFP-LC3B tandem fluorescent protein. BMS-754807 (10μM) significantly induced 22-51% cytotoxicity in all cell lines tested, with E0771 cells showing the strongest response. Treatment with BMS-754807 (2.5µM) significantly increased mitochondrial mass (31%) compared to untreated cells. In addition, co-treatment with BMS-754807 and carboplatin further suppressed cell viability and regulated phosphorylation of the double-stranded DNA damage response proteins γ;-H2AX and Chk2. Co-treatment with BMS-754807 and carboplatin also altered the GFP/RFP ratio in LC3-expressing cells, suggesting modulation of autophagic flux. Finally, the addition of the autophagy inhibitor hydroxychloroquine further induced cytotoxicity when coupled with BMS-754807 and carboplatin. This work indicates that IGF-1R/IR inhibition remodels metabolism in TNBC cells, potentially synergizing with carboplatin to induce double stranded DNA damage. Moreover, the combination of IGF-1R/IR and carboplat