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.