Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer

• Published in: International journal of molecular sciences Vol. 24; no. 2; p. 997
• Main Authors: Bruggemann, Liana, Falls, Zackary, Mangione, William, Schwartz, Stanley A, Battaglia, Sebastiano, Aalinkeel, Ravikumar, Mahajan, Supriya D, Samudrala, Ram
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.01.2023; MDPI
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Computer applications; Disease; Drug Combinations; Drug interaction; Drugs; FDA approval; G12C; Gene expression; Humans; K-Ras protein; Kinases; KRAS; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; MAP kinase; Multiscale analysis; multiscale drug discovery; multitargeting; Mutants; Mutation; Non-small cell lung carcinoma; NSCLC; Pharmaceutical industry; Pharmacogenomics; Phenotypes; Precision medicine; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Proteomics; Proto-Oncogene Proteins p21(ras) - genetics; R&D; Research & development; Synergistic effect; Toxicity; translational bioinformatics; multiscale drug discovery; tyrosine kinase inhibitors; translational bioinformatics; NSCLC; drug synergy; G12C; KRAS; KRAS inhibitors; multitargeting
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24020997

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 using 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 expression is strongly correlated with decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. These results indicate that 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.