MULTISCALE ANALYSIS AND VALIDATION OF EFFECTIVE DRUG COMBINATIONS TARGETING DRIVER KRAS MUTATIONS IN NON-SMALL CELL LUNG CANCER

• Published in: bioRxiv
• Main Authors: Bruggemann, Liana, Falls, Zackary, Mangione, William, Schwartz, Stanley A, Battaglia, Sebastiano, Ravikumar Aalinkeel, Mahajan, Supriya D, Samudrala, Ram
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.11.2022
• Subjects: Computer applications; Drug interaction; K-Ras protein; Lung cancer; Mutants; Non-small cell lung carcinoma; Pharmacogenomics; Phenotypes; Precision medicine; Proteomics; Small cell lung carcinoma; Synergism
• DOI: 10.1101/2022.09.21.508953

Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions with large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors.Validation studies with cellular toxicity assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Gene expression studies revealed that MAPK suppression is a key correlate of decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. Our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales. Competing Interest Statement The authors have declared no competing interest. Footnotes * As osimertinib has a known ability to target ErbB2, which has been implicated in KRAS inhibitor resistance, it is possible inhibition of ErbB2 is responsible for the synergy between ARS-1620 and osimertinib \cite{Liu2018}. Drug/compound concentrations used were partially derived from previously identified GI50/IC50 values \cite{Hillig2019,Janes2018,Cross2014,Misale2019,Liu2018} but non-conformity in compound libraries, time points, and cell lines used makes direct comparisons difficult. Investigation with lower doses of compounds in the nM---pM range, along with with other KRAS G12C mutant cell lines such as H358, is planned for future work as these concentrations are more relevant for use in human patients. Additionally, further experiments at the 72 hour and 96 hour time points with H1792 and other cell lines are planned. * http://data.compbio.org/mc_cando_nsclc/