The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy

Abstract

Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strategies. The origins of antiangiogenic treatment failure may stem from the tumor vasculature, the tumor itself, or both together, and preclinical methods that define resistance are diverse and rarely compared. We performed a literature search of the preclinical methodologies used to examine resistance to VEGF pathway inhibitors and identified 109 papers from more than 400 that use treatment failure as the starting point for mechanistic study. We found that definitions of resistance are broad and inconsistent, involve only a small number of reagents, and derive mostly from in vitro and in vivo methodologies that often do not represent clinically relevant disease stages or progression. Together, this literature analysis highlights the challenges of studying inhibitors of the tumor microenvironment in the preclinical setting and the need for improved methodology to assist in qualifying (and quantifying) treatment failure to identify mechanisms that will help predict alternative strategies in patients.

miR-1266 Contributes to Pancreatic Cancer Progression and Chemoresistance by the STAT3 and NF-κB Signaling Pathways

“… 33 Other mechanisms of resistance, including insensitivity to drug-induced apoptosis, upregulation of DNA repair enzymes, induction of drug-detoxifying mechanisms, stromal proliferation, and reduced angiogenesis, play a crucial role in drug resistance. 34 , 35 , 36 , 37 , 38 , 39 …”

Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

“…Due to this broad activity, we examined sitravatinib treatment effects in several highly variable models of TKI resistance that include clinically-relevant metastasis, something rarely performed in mice (see [27] for review). This included resistant cell lines derived from spontaneous metastasis occurring after the surgical resection of orthotopically implanted tumors [28].…”

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

“…Preclinical models examining antiangiogenic treatment resistance rarely faithfully represent treatment-resistant metastatic progression as it presents in patients after surgery (reviewed in Mastri et al, 2016). We therefore derived several VEGFR TKI-resistant cell lines from metastatic lesions spontaneously arising after the removal of primary orthotopic-implanted tumors in mice (Benzekry et al, 2016).…”

“…Numerous cancer treatments can induce senescence, and antiangiogenic therapy is well-known to induce a broad array of circulating cytokine changes in patients, many of which overlap with common SASP proteins (Jain et al, 2009). However, the durability of this phenotype following treatment resistance and treatment withdrawal has not been examined, nor has senescence been linked to the known metastasis-promoting effects of antiangiogenic therapy (Mastri et al, 2016).…”