Fig. 5

The expression of PD-L1 was influenced via a number of signaling pathways. Activating signals were processed via the ERK signaling pathway (via EGFR; B-Raf proto-oncogene, serine/threonine kinase, BRAF-V600E; mitogen-activated protein kinase kinase 1/2, MEK1/2; mitogen-activated protein kinase kinase 1, MAP2K1; MAP2K2; ERK1/2; mitogen-activated protein kinase 3, MAPK3; mitogen-activated protein kinase 1, MAPK1; and Jun proto-oncogene, c-Jun). Activating signals were processed via the EGFR signaling pathway (via neuroblastoma RAS viral oncogene homolog, NRAS; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, PIK3CA; V-akt murine thymoma viral oncogene homolog, AKT; mechanistic target of rapamycin, MTOR; and STAT3). Also, activating signals were processed via the interferon gamma (IFNG) pathway (via IFNG; interferon gamma receptor 1, IFNGR1; signal transducer and activator of transcription 1, STAT1; and interferon regulatory factor 1, IRF1). Pathway signals converge to activation factors Activator protein 1 (AP1), STAT1, STAT3, and IRF1 leading to transcription of PD-L1 genes. Common pathways were utilized among a number patient-specific simulation models. Patient C9TGAJ (KRAS mutation), patient RDD2UW (KRAS mutation), patient M9GYO4 (MAP2K2 mutation), and patient DFZLO2 (MAP3K1 mutation) involved the ERK activation pathway. Patient P90A0O (BRAF1, TP53 mutations) and patient L8MTGU (KRAS, TP53 mutations) involved the ERK activation and apoptotic pathways