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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Small-molecule inhibitors targeting mono (ADP-ribosyl) transferase Poly(ADP-ribose) polymerase 7 (PARP7) are under investigation for cancer monotherapy and in combination with immune checkpoint blockade.
• Previous research indicated that aryl hydrocarbon receptor agonists (AHRa) could enhance sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 in cell lines with inherent sensitivity.

Purpose of the Study:

• To investigate the synergistic effects of combining PARP7 inhibitors with aryl hydrocarbon receptor agonists in a broader range of tumor cell lines.
• To elucidate the molecular mechanisms underlying the observed synergistic response and its potential to overcome hormone therapy resistance.

Main Methods:

• Treatment of diverse tumor cell lines with PARP7 inhibitors (PARP7i) and/or aryl hydrocarbon receptor agonists (AHRa).
• Assessment of synergistic sensitivity to combination therapy.
• Analysis of aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) pathway activation, including nuclear AHR levels and AHR target gene transcription.
• Investigation of steroid hormone receptor (androgen receptor, estrogen receptor) degradation via proteasomal pathways in hormone receptor-positive cell lines and cancer models.

Main Results:

• Tumor cell lines insensitive to individual PARP7i or AHRa treatments exhibited profound sensitivity to their combination, indicating a synergistic effect.
• The synergistic response was dependent on the AHR/ARNT pathway, evidenced by increased nuclear AHR and elevated transcription of AHR target genes.
• Combination treatment led to the proteasomal degradation of both wild-type and hormone-resistant mutant forms of androgen receptor and estrogen receptor in breast and prostate cancer models.

Conclusions:

• The combination of PARP7 inhibitors and aryl hydrocarbon receptor agonists demonstrates significant synergistic anti-tumor activity across a wider spectrum of tumors than either agent alone.
• This combination strategy shows potential for overcoming hormone therapy resistance by inducing the degradation of key steroid hormone receptors.
• Combining PARP7i with AHRa may represent a promising therapeutic approach for treating hormone-dependent cancers, including those refractory to current hormone therapies.