Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced Igf1r in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.

Advanced age and obesity are major risk factors for breast cancer progression, including triple-negative breast cancer (TNBC). In this study, we interrogated (i) whether these factors interact to promote TNBC progression and (ii) whether weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity interact to promote TNBC growth in mice. Transcriptomic analysis revealed the suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction reduced tumor growth and restored immune-related gene signatures to reverse the protumor effects of aging and/or obesity. Using publicly available genomic datasets from murine studies of obesity, weight loss, and TNBC, we identified a consensus transcriptomic signature of obesity-driven immunosuppression that predicted the survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. Intermittent calorie restriction reversed the effects of aging and/or obesity on the consensus signature. We conclude that aging and obesity interact to limit antitumor immunity and enhance TNBC progression and that these adverse effects can be disrupted by weight loss. Prevention Relevance: Advanced age and obesity are important risk factors for the development and progression of breast cancers, including TNBC. We demonstrate that the suppression of signatures of antitumor immunity is a common feature of accelerated tumor progression in TNBC. We show that weight loss achieved through calorie restriction can restore such markers.

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.

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-Wnt^lung, 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 carboplatin can further collaborate with autophagy inhibition to strongly suppress TNBC cell growth. We conclude that inhibiting nutrient-sensing metabolic pathways such as IGF-1R/IR in combination with chemotherapy and/or autophagy inhibition warrants additional study as a strategy to improve therapeutic responses in women with TNBC. Citation Format: Alyssa N. Ho, Violet A. Kiesel, Scott P. Connelly, Michael F. Coleman, Stephen D. Hursting. Targeting metabolic pathways through pharmacological and chemotherapeutic interventions to improve triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3010.

Advanced age and obesity are major risk factors for breast cancer progression, including triple-negative breast cancer (TNBC). In this study, we interrogated (i) whether these factors interact to promote TNBC progression and (ii) whether weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity interact to promote TNBC growth in mice. Transcriptomic analysis revealed the suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction reduced tumor growth and restored immune-related gene signatures to reverse the protumor effects of aging and/or obesity. Using publicly available genomic datasets from murine studies of obesity, weight loss, and TNBC, we identified a consensus transcriptomic signature of obesity-driven immunosuppression that predicted the survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. Intermittent calorie restriction reversed the effects of aging and/or obesity on the consensus signature. We conclude that aging and obesity interact to limit antitumor immunity and enhance TNBC progression and that these adverse effects can be disrupted by weight loss.Prevention Relevance:Advanced age and obesity are important risk factors for the development and progression of breast cancers, including TNBC. We demonstrate that the suppression of signatures of antitumor immunity is a common feature of accelerated tumor progression in TNBC. We show that weight loss achieved through calorie restriction can restore such markers.See related Spotlight, p. 437