EGFR (exon 19, 20 and 21) and KRAS (exon 2) mutations were detected using an amplification refractory mutation system technique, and the expression of VEGFA, VEGFR1 and VEGFR2 was analyzed using immunohistochemistry in 204 patients with lung adenocarcinoma.
Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes.<b>Results:</b> Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment.
Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti-VEGFR-1/2/3, platelet-derived growth factor receptor-α/β, fibroblast growth factor receptor-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union.
Furthermore, we demonstrated for the first time that the inhibition of EZH2 greatly increased the sensitivity of lung adenocarcinoma cells to the anti-VEGFR-2 drug AZD2171.
These findings imply that angiogenesis and phenotypic changes of the alveolar capillaries are closely related to a higher expression of tumor-associated VEGF165 and of KDR in the alveolar walls in primary lung adenocarcinoma.