Abstract B178: Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs

Abstract

Abstract While poly-ADP-ribosylation (PAR) polymerase inhibitors (PARPi) are the only DNA damage repair (DDR) agent currently approved for clinical use, there are numerous ongoing clinical and preclinical drug development efforts of many other DDR-related targets, including ATR, ATM, CHK1 and others. One of the major challenges of these efforts is the ability to identify responsive populations and assign the right population for the right drug or drug combination. Patients are routinely assigned to PARPi or to on-going DDRi clinical trials based on the presence of BRCA mutation, or BRCAness profile encompassing various homologous recombination deficiencies (HRD). However, these biomarkers only partially represent the responsive populations, resulting in low response rates as well as misidentification of potential patient populations outside the genomic label. Since DNA replication and DNA repair mechanisms are dominated by signaling events, we hypothesized that HRD extends beyond the genomic status, and is manifested also in the level of protein expression and protein modification.In the current work, we compare the differences between cell lines that are either sensitive or resistant to a variety of DDR agents and highlight potential predictive biomarkers that are independent of HRD mutation status. We combined publicly available proteomic profiles of unperturbed cell lines, with both existing and newly generated proteomic and phosphoproteomic data of multiple cell lines before and after treatment of multiple DDR drugs.Analysis of HRD mutations showed that drug sensitivity is only partially explained by mutations. In addition, we found DNA replication and spliceosome as pathways that are consistently related to response regardless of drug and mutation status. While there is a general agreement between drugs in the pathway level, we identify smaller groups of proteins that are either drug or target-specific. We present here a proteogenomic approach to tackle the challenge of predictive biomarkers to DDR drugs. While DNA repair vulnerability is essential for DDR drug response, it is often not defined by mutations alone. We provide a proteomics-based framework that would enable future patient selection in DDR clinical trials. Citation Format: Gali Arad, Avital Hay-Koren, David Futorian, Oren Fischman, Dina Daitchman, Ofer Givton, Iris Alchanati, Yonatan Katzenelenbogen, Eran Seger, Kirill Pevzner. Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B178.