PARP7 Inhibitors and AHR Agonists Act Synergistically across a Wide Range of Cancer Models

Abstract Small-molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated asmonotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by cotreatment with agonists of the aryl hydrocarbon receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. In this study, we demonstrated that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to their combination. Our data show that this synergistic response is dependent on the AHR/AHR nuclear translocator and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor–positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wild-type and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.