Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model

Abstract

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows superior efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (EGFR Mut+). However, almost all tumors eventually develop resistance to erlotinib. Recently, the Phase II JO25567 study reported significant prolongation of progression-free survival (PFS) by erlotinib plus bevacizumab combination compared with erlotinib in EGFR Mut+ NSCLC. Herein, we established a preclinical model which became refractory to erlotinib after long-term administration and elucidated the mode of action of this combination. In this model, tumor regrowth occurred after remarkable shrinkage by erlotinib; regrowth was successfully inhibited by erlotinib plus bevacizumab. Tumor vascular endothelial growth factor (VEGF) was greatly reduced by erlotinib in the erlotinib-sensitive phase but significantly increased in the erlotinib-refractory phase despite continued treatment with erlotinib. Although EGFR phosphorylation remained suppressed in the erlotinib-refractory phase, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were markedly higher than in the erlotinib-sensitive phase; among these, pERK was suppressed by erlotinib plus bevacizumab. MVD was decreased significantly more with erlotinib plus bevacizumab than with each drug alone. In conclusion, the erlotinib plus bevacizumab combination demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. Re-induction of VEGF and subsequent direct or indirect VEGF-dependent tumor growth was suggested as a major mechanism of erlotinib resistance, and erlotinib plus bevacizumab achieved remarkably prolonged antitumor activity in this model.

Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer‐associated fibroblasts with EGFR‐TKI resistance‐promoting phenotype: A study of 18 cases of cancer‐associated fibroblasts

“…HGF, IL‐6, IGF‐1, VEGF‐A, and FGF‐2 have been reported to induce EGFR‐TKI resistance . To identify the responsible humoral factors, involved in the resistance found in the current study, we compared expression level of these cytokines between resistant group ( n = 5; case1, 3, 8, 11, and 17) and non‐resistant group ( n = 13; case 2, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, and 18).…”

“…In the case of VEGF‐A, anti‐VEGF antibody (Bevacizumab) treatment and EGFR‐TKI treatment reduced phosphorylation status in EGFR downstream signaling. Moreover, this combination therapy showed improved outcome compared to EGFR‐TKI monotherapy, in the xenograft model . We compared the mRNA expression of IL‐6, IGF‐1, FGF‐2, and VEGF‐A between the resistant group and non‐resistant group.…”

“…In the case of humoral factors, previous reports have shown that hepatocyte growth factor (HGF) derived from CAFs enhanced EGFR‐TKI resistance . Moreover, interleukin‐6 (IL‐6), fibroblast growth factor‐2 (FGF‐2), insulin‐like growth factor‐1 (IGF‐1), and vascular endothelial growth factor‐A (VEGF‐A), produced by peripheral stromal cells or cancer cells on their own, also cause EGFR‐TKI resistance in lung cancer patients harboring EGFR mutations …”

Bevacizumab suppresses the growth of established non-small-cell lung cancer brain metastases in a hematogenous brain metastasis model

“…TV was estimated from the equation TV = ab 2 /2, where a and b are tumor length and width, respectively. Bevacizumab or HuIgG was intraperitoneally administered once a week at a dose of 5 mg/kg (days 1, 8, and 15), based on the regimen in a previous report [21]. To evaluate the antitumor activity, TV and Nluc activity were measured on day 22.…”

Comparison of tumor related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma

“…EGFR‐tyrosine kinase inhibitors (TKIs) have become an indispensable therapeutic strategy in advanced NSCLC patients with EGFR sensitive mutations, such as those in exons 19 and 21. Nevertheless, drug resistance frequently occurs during therapy, minimizing the ability to control disease progression . Urgent investigation of the pathways related to the mechanisms of drug resistance is being conducted to determine the critical biological agents of this process.…”