Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC

Abstract

Background The identification of early plasma biomarkers for clinical outcomes and drug resistance has key importance for risk stratification in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients. Moreover, it remains unclear whether the anti-angiogenic drug anlotinib can reverse the resistance of ALK-tyrosine kinase inhibitor (ALK-TKI) crizotinib, and no research has explored the effect of anlotinib combined with crizotinib on ALK-positive patients. Methods In this study, 76 baseline and longitudinal plasma samples from 61 ALK-positive NSCLC patients receiving crizotinib treatment were analyzed by Luminex liquid suspension chip for 40 chemokines. RNA sequence (RNA-seq) was used to identify differentially expressed genes (DEGs) between H3122 and H3122-crizotinib resistant (H3122CR) cells. Tube formation assay was performed to investigate the effect of chemokines on angiogenesis. And H3122CR-derived xenograft model was constructed to validate the efficacy and safety of anlotinib combined with crizotinib in vivo. Results Baseline and progression plasma samples detection suggested that CCL20 played a crucial role in monitoring and predicting the clinical response of crizotinib (hazard ratio for progression-free survival: 2.27 (1.13–4.58); for overall survival: 2.7 (1.23–5.8)). RNA-seq results for H3122 and H3122CR cells showed that high expression of chemokines and angiogenesis pathways were involved in crizotinib resistance. Subsequently, in vitro experiments indicated that CCL20 may induce crizotinib resistance by activation of angiogenesis via JAK2/STAT3-CCL20-VEGFA/IL6 axis. We further found that anti-angiogenic TKI anlotinib could reverse crizotinib resistance by inhibiting chemokines-induced angiogenesis, and anlotinib combined with crizotinib has a better antitumor effect than monotherapy in vitro & in vivo. Conclusions Overall, CCL20-mediated angiogenesis is involved in crizotinib resistance and could be overcome by using anlotinib in EML4-ALK positive NSCLC. The combination of anlotinib and crizotinib is a promising strategy for patients resistant to ALK-TKIs.

Case Report: Long-term remission of malignant pleural and peritoneal effusion in a case of advanced lung adenocarcinoma treated with combined crizotinib and anlotinib therapy

“…This multitarget inhibition mechanism may lead to a more comprehensive anti-tumor effect and improved treatment outcomes, particularly in tumors with multiple aberrant signaling pathways. Additionally, combining Anlotinib with Crizotinib may help overcome resistance observed with Crizotinib monotherapy by suppressing chemokine-mediated angiogenesis and enhancing the overall anti-tumor efficacy ( 11 ). However, it is important to note that the combined use of Anlotinib and Crizotinib may increase the risk of adverse reactions, as both drugs have their own side effect profiles including hypertension, hand-foot syndrome, fatigue, and gastrointestinal discomfort.…”

CXCR7 promotes pulmonary vascular remodeling via targeting p38/MMP2 pathway in pulmonary arterial hypertension

“…The chemokine system consists of around 50 ligands and 20 receptors in humans, and takes part in many aspects of central nervous system development ( 4 ), tumorigenesis ( 5 ), and angiogenesis ( 6 , 7 ). The C-X-C motif chemokine family has received increased attention due to its role in PAH.…”