Fig. 1: Simplified model of the chosen combination therapy regimen overcoming drug resistances by simultaneous targeting of interdependent signaling in the c Cellular Tumorigenic Network of NSCLC tumors using already marketed drugs.

Signaling axes of VEGF-VEGFR, EGF-EGFR, SDF-1-CXCR4, HGF-MET, COX2-PGE2-EP, and PD-1-PD-L1 are exemplary shown for some of the known paracrine pathways binding the Cellular Tumorigenic Network in NSCLC tumors. Evidence is provided that resistances to targeted therapy drugs are partly based on substitutions for inhibited pathways and on crosstalk of generic intracellularly connected downstream pathways involved in tumor development and treatment resistance such as MAPK, JAK/STAT, PI3K, AKT, and PKC¹¹. Therefore, combined targeted therapies against selected pathways may overcome primary and secondary drug resistances. The combination therapy drugs cabozantinib, afatinib, plerixafor, and etoricoxib are provided adjacent to the respective targeted pathways (figure under Creative Commons Attribution 3.0 License updated from Langhammer and Scheerer, 2017⁷). PGE2, prostaglandin E2; VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; COX2 (PTGS2), cyclooxygenase 2; HGF, hepatocyte growth factor; red circle: tumor neo-antigen.