Breaking the Crosstalk of the Cellular Tumorigenic Network in NSCLC by a Highly Effective Drug Combination

Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages limiting treatment options. Although, targeted therapy has become integral part of NSCLC treatment therapies often fail to improve patient’s prognosis. Based on previously published criteria for selecting drug combinations for overcoming resistances, NSCLC patient-derived xenograft (PDX) tumors were treated with a low dose combination of cabozantinib, afatinib, plerixafor and etoricoxib. All PDX tumors treated, including highly therapy-resistant adeno-and squamous cell carcinomas without identifiable driver mutations, were completely suppressed by this drug regimen, leading to an ORR of 81% and a CBR of 100%. The application and safety profile of this low dose therapy regimen was well manageable in the pre-clinical settings. Overall, this study provides evidence of a relationship between active paracrine signaling pathways of the cellular tumorigenic network, which can be effectively targeted by a low-dose multimodal therapy to overcome therapy resistance and improve prognosis of NSCLC. ### Competing Interest Statement The authors Theresia Conrad, Michael Becker, Susanne Sebens and Christoph Roecken declare no conflict of interest. Jens Hoffmann, Dennis Guergen and Stefan Langhammer have issued a related patent, PCT/EP2021/072486. Jens Hoffmann declares the employment and the ownership of the EPO GmbH.