Novel Dual Inhibitors of PARP and HDAC Induce Intratumoral
STING-Mediated Antitumor Immunity in Triple-Negative Breast Cancer
Abstract
Background and Purpose: PARP and HDAC inhibitors are approved for the
clinical treatment of malignancies, but acquired resistance or limited
effects on solid tumors with single-agent present challenges. Therefore,
there is an urgent need to design and synthesis of dual inhibitors
involving a different mechanism of action can provide new treatments.
Experimental Approach: We validate the correlation and synergy between
PARP and HDAC by database analysis and colony formation assay. Novel
dual PARP and HDAC inhibitors antitumor effects in vitro were validated
by flow cytometry and cell biology analysis. Pharmacological
characterization was characterized by enzymatic inhibition assays, cell
viability assays, western blot, real-time PCR, immunofluorescence
analyses. The antitumor effect in vivo was validated in MDA-MB-436 and
4T1 xenograft mouse models. Key Results: Bioinformatics analyses and a
combination of experiments demonstrate the synergistic effects of PARP
and HDAC inhibitors in triple-negative breast cancer. Novel dual PARP
and HDAC inhibitors were rationally designed and synthesized, and
exhibited high enzyme inhibition activity, showing excellent antitumor
effects in vitro and in vivo. Mechanistically, dual PARP and HDAC
inhibitors significantly induced BRCAness to restore synthetic lethality
and the accumulation of cytosolic DNA to activate the cGAS–STING
pathway and produce proinflammatory chemokines through type Ⅰ
IFN-mediated JAK–STAT signaling. Moreover, these inhibitors promoted
neoantigen generation and upregulated antigen presentation genes and
PD-L1. Conclusion and Implications: Novel dual PARP and HDAC inhibitors
showing excellent antitumor effect via the activation of the tumoral IFN
signaling and cytokine production to enhance the immune response for
triple-negative breast cancer.