Cellworks Omics Biology Model (CBM) to identify amplifications of chromosome 11p and 1p predict paclitaxel and carboplatin resistance.
Authors: Castro Michael , Kumar Ansu , Grover Himanshu , Patil Vivek , Nair Prashant , Chafekar Srushti P , Suseela Rakhi Purushothaman , Prasad Samiksha , Kumar Chandan , Joseph Vishwas , Mundkur Nirjhar , Kumari Pallavi , Pampana Anusha , P S Vijayashree , Choudhary Ashish , Balakrishnan Veena , Husain Zakir , Balla Ashokraja , Ganesh Naga , Velcheti Vamsidhar 
Published: June 2021

e21208

Background: Paclitaxel and carboplatin (PC) is used to treat a wide variety of malignancies including gynecologic, breast, lung, and occult primary cancers. In NSCLC, PC led to a substantial improvement in 1-yr survival from 10% (P alone) to approximately 50% seen with the combination. Nevertheless, a large proportion of patients do not respond. An optimal cytotoxic strategy for managing NSCLC and the discovery of chemotherapy biomarkers to guide treatment selection remain unmet needs in the clinic. Cellworks CBM platform identified a unique chromosomal signature which permits a stratification of which patients are most likely to respond to PC treatment. Methods: 22 patients treated with PC were published in TCGA dataset and selected for analysis. The mutation and copy number aberrations from individual cases 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. Digital drug simulations were conducted by measuring effect of PC on a cell growth score comprised of a composite of cell proliferation, apoptosis, and other cancer hallmarks. Drug simulations were systematically conducted to identify and evaluate therapeutic efficacy. The drug combination was mapped to the patient genome along with a rational mechanism of action and validated based on the genomic profile and its biological consequences. Results: Of the 22 patients treated with PC, 13 had clinical responses and 9 were non-responders. The computer simulation correctly predicted response in 16/22 with 72.73% accuracy, 55.56% specificity and 84.62% sensitivity. CBM identified novel amplified segments of Chromosome 11p and 1p were responsible for non-responsiveness to PC. Key genes on these chromosomes were identified belonging to the autophagy, reactive oxygen species (ROS) scavenging, DNA repair, and microtubule polymerization pathways. Amplification of AMBRA1, ATG13 and TRAF6 (11p) led to autophagy upregulation resulting in low ROS level, a well-documented resistance loop for chemotherapy. SIRT3 and CAT (11p), ROS scavenging genes, were also upregulated due to increase in copy number. CTH (1p) is another key enzyme involved in GSH-mediated ROS scavenging and was also upregulated. Biosimulation indicated a low ROS level was the key reason of resistance to PC. Heightened DNA damage repair due FANCF and ZNF143 (11p amp) and USP1 (1p amp), was another cause of PC resistance. These discoveries suggest that a combination of an autophagy inhibitor / BCL2 mimetic might prove useful to reverse PC resistance associated with 11p and 1p amp. Conclusions: This study highlights how CBM simulation platform can help to identify novel patient segments for therapy response prediction and use drug re-purposing to overcome chemotherapy resistance.