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

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. The identification of novel therapeutic strategies for advanced non-small cell lung cancer (NSCLC) is essential as the outcome of most of these patients is poor. Here the authors provide a proof-of concept that specific low-dose drug combinations can disrupt intercellular crosstalk to overcome drug resistance in NSCLC patient-derived xenografts.

Automated summary

This study provides evidence that low-dose multimodal therapy can effectively overcome drug resistance and improve prognosis in non-small cell lung cancer patients.