Identification of a Two-Gene Biomarker Correlated with Sensitivity to Combined PARP7 Inhibition and AHR Activation in Cancer Cells.

[UNLABELLED] PARP7 inhibitors (PARP7i) and aryl hydrocarbon receptor agonists (AHRa) can synergistically suppress growth of some cancer cell lines but not others. In this study, we derived a two-gene transcriptional score to predict the synergistic response and characterized the molecular, immune, and prognostic features of this biomarker. Cancer cells were categorized into synergistic and nonsynergistic cell lines based on synergy scores that we previously reported. Published RNA sequencing data were used to establish a biomarker for PARP7i and AHRa synergistic response that was comprised of the expression of the two most differentially expressed immune-related genes (CCL22 and TNFSF10). This biomarker was successfully validated in an independent set of cell lines. An integrated multiomics analysis revealed that synergistic lines had increased expression of immune-related gene sets and low expression of epithelial-mesenchymal transition-associated genes and co-expression network analysis identified transcription factors associated with synergy. In The Cancer Genome Atlas patients with breast and prostate cancers, biomarker genes were correlated with immune cell infiltration. Receiver operator characteristic (ROC) and hazard ratio (HR) analyses demonstrated that the biomarker score was correlated with response to anti-programmed cell death protein 1 (PD-1) therapy in a cohort of patients with kidney cancer and correlated with better overall survival in patients with cancer treated with anti-programmed cell death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. In summary, we have identified a transcriptional biomarker that predicts cellular response to PARP7i and AHRa combination therapy, which is associated with benefits from immune checkpoint inhibitor therapies in patients with cancer.

[SIGNIFICANCE] We employed a multiomic approach to identify a transcriptional biomarker that is predictive of cellular response to combined treatment with PARP7i and AHRa. The molecular, immune, and prognostic characterizations of this biomarker may provide insights into the molecular mechanisms of response and aid in stratifying patients likely to benefit from this combination therapy.