Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models

Abstract

Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells’ self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer.

Special Issue: Cancer Metastasis and Therapeutic Resistance

“…This issue had a significant set of original research, tackling different aspects of breast cancer. The article by Barutello et al examines a combination of methods to target the cystine-glutamate antiporter xCT and p53 using the drug APR-246, which restores the wildtype function of p53 in mutant p53 tumors [6]. xCT is an emerging target in breast cancer that ties cancer cell metabolism to redox regulation [7].…”

“…xCT is an emerging target in breast cancer that ties cancer cell metabolism to redox regulation [7]. Findings from Barutello et al suggest that the combined targeting of xCT and p53 is effective at decreasing breast cancer cell viability and CSC self-renewal [6]. Furthermore, to study the in vivo effect of the combined targeting of xCT and p53, the authors immunized mice against xCT and co-treated them with APR-246.…”