Breaking the crosstalk of the Cellular Tumorigenic Network by low-dose combination therapy in lung cancer patient-derived xenografts

Dennis Gürgen,Christoph Röcken,Michael Becker,Susanne Sebens,Stefan Langhammer,Jens Hoffmann,Theresia Conrad

doi:10.1038/s42003-022-03016-5

Abstract

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 targetable oncogenic 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.

Highlights

Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages limiting treatment options
NSCLC patients without targetable oncogenic mutations and without Programmed death ligand-1 (PD-L1) expression are still a major challenge and there is a need for experimental generation of new, rational combination strategies with targeted therapies addressing factors of the Cellular Tumorigenic Network[6,7], as apart from the tumor cells, non-neoplastic cells such as cancerassociated fibroblasts, endothelial cells, and immune cells contribute to tumor growth
In order to assess the five criteria postulated for overcoming drug resistances 38 well characterized patient-derived, human NSCLC tumor xenograft models (PDX) from the EPO patient-derived xenograft (PDX) panel were analyzed for mRNA expression of (i) paracrine signaling pathways mediating intercellular interdependency within the Cellular Tumorigenic Network that were (ii) non-overlapping and have been described (iii) as relevant for tumor proliferation previously and druggable by approved inhibitors[6]

Summary

Introduction

Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages limiting treatment options. Most cases of non-small cell lung cancer (NSCLC) are diagnosed at advanced metastasized stages and indicated for palliative treatment These mainly nonresectable carcinomas are treated with platinum-based chemotherapy alone or in combination with immune-checkpoint inhibitors, which are the mainstay regimens in the absence of predictive, targetable oncogenic mutations and an expression of the immune-checkpoint inhibitor Programmed death ligand-1 (PD-L1) of

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Conclusion