Identification of a two-gene biomarker correlated with sensitivity to combined PARP7 inhibition and AHR activation in cancer cells

PARP7 inhibitors (PARP7i) and AHR agonists (AHRa) can synergistically suppress growth of some cancer cell lines, but not others. Here, we derived a two-gene transcriptional score to predict the synergistic response and characterized the molecular, immune and prognostic features of this signature. Cancer cells were categorized into synergistic and non-synergistic cell lines based on synergy scores that we previously reported. Published RNA sequencing (RNA-seq) data was 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 multi-omics analysis revealed that synergistical lines had increased expression of immune-related gene sets and low expression of epithelial-mesenchymal transition (EMT)-associated genes and co-expression network analysis identified transcription factors (TFs) associated with synergy. In The Cancer Genome Atlas (TCGA) breast and prostate cancer patients, biomarker genes were correlated with immune cell infiltration. Receiver Operating Characteristic (ROC) and Hazard Ratio (HR) analyses demonstrated that the biomarker score was correlated with response to anti-PD-1 therapy in a cohort of kidney cancer patients and correlated with better overall survival (OS) in cancer patients treated with anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-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 (ICI) therapies in cancer patients.