EGFR mutations are a key therapeutic target in non-small cell lung cancer (NSCLC) carrying somatic mutations in the structural domain of EGFR tyrosine kinase. These EGFR mutations cause activation of STAT and Akt signaling pathways, both of which together promote cell survival. In addition, modulation through ERK signaling may cause downregulation of pro-apoptotic BH3-only proteins (e.g., BCL2L11). EGFR tyrosine kinase inhibitors, such as erlotinib or gefitinib, are the standard of care for patients with EGFR-mutated NSCLC. However, their median progression-free survival still does not exceed 10 months, and combination therapies have not been incorporated into clinical practice to overcome potential mechanisms of resistance to EGFR tyrosine kinase inhibitor monotherapy, such as EGFR Thr790Met mutations2,4 and MET amplification. Interestingly, erlotinib has been reported to induce MET-independent activation of STAT3 survival signaling in EGFR-mutated lung cancer cells. STAT3 promotes the expression of oncogenes, such as BCL2 and BCL-XL, as well as the expression of some other genes involved in pro-angiogenesis, such as HIF1A. anti-VEGF antibodies, such as bevacizumab, are approved by the European Medicines Agency for their use in several cancer types. In Lancet Oncology, Takashi Seto and colleagues report on a randomized phase 2 study in patients with EGFR-mutated NSCLC that examined the potential benefit of adding bevacizumab to erlotinib compared with erlotinib alone. There was an important difference in progression-free survival between the two, with 9.7 months (95% Cl 5.7-11.1) for patients given erlotinib alone and 16 months (13.9-18.1) for erlotinib combined with bevacizumab, with a hazard ratio of 0.54 ([95% Cl 0.36-0.79]; p=0.0015) for both compared. The increase in progression-free survival constitutes a new hallmark in the treatment of patients with non-small cell lung cancer with EGFR mutations, where side effects of bevacizumab such as hypertension and proteinuria are manageable. Thus, the study represents a new approach to optimizing the treatment of patients with non-small cell lung cancer with EGFR mutations. The researchers hypothesized that the benefit of bevacizumab was associated with anti-angiogenic effects normalizing tumor vasculature and possibly enhancing erlotinib-tumor contact. In addition, inhibition of VEGF signaling by bevacizumab contributed to attenuate the induction of STAT3 phosphorylation by erlotinib. Paradoxical activation of STAT3 by erlotinib is a novel and surprising result for enhancing standard EGFR tyrosine kinase inhibitor therapy that requires further investigation. The study by Seto and colleagues strongly demonstrated that the combination of erlotinib with bevacizumab significantly increased progression-free survival compared to erlotinib alone. This new therapeutic strategy targeting VEGF may emerge as novel tolerogenic, as VEGF directly and negatively regulates tumor cell invasion by creating a MET/VEGFR2 heterodimer that inhibits HGF-dependent, Met phosphorylation and tumor cell migration. In glioblastoma, VEGF repair can be inhibited and MET activity can be increased. Interestingly, the triple inhibition of EGFR, MET and VEGF reversed the resistance of erlotinib in EGFR mutant cell lines. The combination of erlotinib, crizotinib (a MET and ALK inhibitor) and bevacizumab successfully inhibited erlotinib-resistant tumor growth in EGFR-mutated cell lines. Thus, the complexity of the signaling pathway, and the interference between preclinical and clinical findings, opens the door to novel therapies including oral pan-tyrosine kinase inhibitors targeting primarily VEGF and MET. Other studies, such as BELIEF, are using the combination of erlotinib and bevacizumab as the primary target to clarify the role of this combination in patients carrying EGFR Thr790Met mutations in non-small cell lung cancer. the study by Seto and colleagues is likely to pave the way for a shift from EGFR tyrosine kinase inhibitor monotherapy to combination therapy to improve EGFR-mutated non-small cell lung cancer prognosis. If the clinical benefit of EGFR tyrosine kinase inhibitors in combination with VEGF-targeted therapy is further confirmed, next studies could be completed to prevent possible novel mechanisms of VEGF-resistant targeted therapy, such as galectin-1 expression, where galectin-1 prolongs the cell surface residence of VEGFR2 and stimulates VEGF-dependent tumor angiogenesis. galectin-1 neutralizing antibody-specific prevention of galectin-1-induced angiogenesis is an interesting phenomenon. In conclusion, the understanding of lung cancer biology has been advancing and its treatment is becoming increasingly complex. Therefore, the rapid development of more adequately targeted therapies with more detailed analysis of tumor molecular biology is urgently needed.