Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Background: Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages with limited treatment options particularly in tumors without targetable driver mutations.</jats:p>
<jats:p>Methods: Considering previously published criteria for selecting drug combinations for overcoming drug resistances1, we have established a low dose combination therapy with cabozantinib, afatinib, etoricoxib and plerixafor. Utilizing NSCLC patient-derived xenograft (PDX) models we aimed to use this drug regimen to disrupt paracrine substitutional signaling within the tumorigenic network in order to circumvent pre-existing and adaptive drug resistances. In contrast to daily dosing for respective monotherapies the low dose treatment was paused every five days for two days.</jats:p>
<jats:p>Result: 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 Objective Response Rate of 81% and a Clinical Benefit Rate of 100%. After treatment discontinuation growth suppression remained until the end of the follow-up period with only slight increase in tumor growth. The application and the safety profile of this low dose therapy regimen was well manageable and without pronounced side effects in this pre-clinical setting.</jats:p>
<jats:p>Discussion: For the first time we show that simultaneous inhibition of pathways forming the cellular tumorigenic network in NSCLC tumors is highly effective and overcomes drug resistances for monotherapies. All of the drugs used in this combination regimen are approved for different indications and therefore readily available. Conclusion: Our results emphatically encourage a setup for a clinical study in advanced stage NSCLC patients without targetable driver mutations combining the drugs cabozantinib, afatinib, plerixafor and etoricoxib in a low dose treatment regimen as novel therapy strategy.</jats:p>
<jats:p>Indication of Source: 1. Langhammer S and Scheerer J. Oncotarget 8, 43555-43570 (2017).</jats:p>
<jats:p>Citation Format: Dennis Gürgen, Theresia Conrad, Michael Becker, Susanne Sebens, Christoph Röcken, Jens Hoffmann, Stefan Langhammer. Breaking the crosstalk of the cellular tumorigenic network in NSCLC by a highly effective drug combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3095.</jats:p>