Cellworks Omics Biology Modeling (CBM) to predict therapy response and identifies novel biomarkers for carboplatin/cisplatin along with pemetrexed in NSCLC patients.

Abstract

e21211 Background: Cancer management using cytotoxic drugs is hampered by limited efficacy. Hence, a personalized treatment approach matching chemotherapy with appropriate patients remains a persistent and unmet need in the clinic. Genomic heterogeneity among patients creates an opportunity to discern key genomic aberrations and pathways that confer resistance and response to standard treatment options. Pemetrexed, an antifolate, primarily inhibits thymidylate synthase (TYMS) while platinum compounds (carboplatin/cisplatin) trigger DNA damage similar to alkylating agents. When the DNA damage exceeds repair, apoptosis results. We conducted a pilot study using CBM to novel genomic biomarkers of response and resistance to pemetrexed–platinum treatment. Methods: 25 patients who received pemetrexed–platinum therapy were selected from TCGA data. Mutation and copy number aberrations from each case served as input into the CBM (generated from PubMed and other online resources) to create a patient-specific protein network map. Disease-biomarkers unique to each patient were identified within protein network maps. Drug impact on the disease network was digitally simulated to determine treatment efficacy by measuring effect of chemotherapy on the cell growth score, i.e., a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. Effectively, the mechanism of action of each drug was mapped to each patient’s genome and biological consequences due to genomic abnormalities were correlated with response. Results: Among the 25 patients, 23 responders (R) and 2 non-responders (NR). The computer simulation correctly predicted response in 19/25 with 76% accuracy, 100% specificity and 73.91% sensitivity. CBM identified co-occurrence of deleted segments of chromosome 6q, 13q, 14q and 17q were responsible for pemetrexed-platinum response. The key genes governing response on these chromosomes included drug transporters and DNA repair pathways. ATP7B (13q) which exports platinum-based drugs was deleted in responders. The loss of REV3L (6q ), MBD1 (6q ), ERCC1 (6q), BRCA2 (13q), BRCA1 (17q), FANCM (14q), RAD51B (14q), XRCC3 (14q ) led to failure of DNA repair. RB1 (13q) del also led to failure of BRG1 mediated DNA repair . Combinations of these repair genes and transporters formed the major response criteria among the 23 responders while these characteristics were absent in non-responders. Conclusions: This pilot study highlights how CBM simulation platform can identify patients for therapy response prediction. Copy number changes impact responsiveness to chemotherapy and should be routinely assessed. We suggest that this approach should be validated prospectively in a larger patient cohort.