Dual mechanisms of PARP7 inhibition driving potent antitumor activity

PARP7 is a mono-ADP-ribosyltransferase that transfers a single ADP-ribose moiety to its substrates, thereby modulating protein function and contributing to the regulation of type I interferon (IFN) signaling and cellular homeostasis. In cancer models, PARP7 inhibition exhibits strong antitumor activity through a dual mechanism involving activation of the type I IFN pathway and direct tumor-intrinsic effects within cancer cells. We have developed a couple of series of novel PARP7 inhibitors, and in this study, we focused on characterizing the molecular features associated with responsiveness to PARP7 inhibitors in parallel with mechanistic studies using the clinical-stage benchmark, RBN-2397. First, in the context of antitumor immune activation, we hypothesized that interferon-stimulated gene (ISG) induction upon PARP7 inhibition is positively correlated with antitumor activity. In mouse syngeneic models, cancer cells showing strong ISG induction upon PARP7 inhibition exhibited greater antitumor responses. Combination with chemotherapeutic agents that increase cytosolic double-stranded DNA (dsDNA) further enhanced ISG induction and antitumor activity. To define ISG induction responsiveness, we screened more than 40 human cancer cell lines and categorized them as ISG responders or non-responders. Responders exhibited gene expression patterns characterized by elevated innate immune signaling and reduced genome stability. In addition to its immuno-oncological activity, PARP7 inhibition exerts an intrinsic, cell-autonomous antitumor effect, suggesting a dual mechanism of action for PARP7-targeted therapy. This intrinsic cytotoxic effect acts independently of the catalytic inhibition responsible for immune activation. While multiple mechanisms have been proposed, our data support that a PARP7 inhibitor-induced chromatin-associated trapping process represents a critical event leading to nuclear accumulation of PARP7 and subsequent DNA damage. Additionally, we confirmed that intracellular PARP7 expression is essential for PARP7 inhibitor-induced cytotoxicity. Furthermore, using the CRISPR-Cas9 system, we validated an additional key factor involved in this intrinsic cytotoxicity. Collectively, our findings demonstrate that PARP7 inhibition elicits a dual mechanism involving ISG induction and intrinsic cytotoxicity, resulting in robust antitumor activity. The key regulatory factors underlying this dual mechanism may serve as potential biomarkers for patient selection in future clinical trials and help identify individuals most likely to benefit from PARP7-targeted therapy.