VEGF Signal Complexity Confers Resistance to Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in EGFR‐Tyrosine Kinase Inhibitor‐Resistant Non‐Small Cell Lung Cancer

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) therapy is beneficial for epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI)‐resistant non‐small cell lung cancer (NSCLC); however, the resistance mechanisms are not fully understood. In this study, we conducted a single‐cell RNA‐sequencing analysis of EGFR‐TKI‐resistant NSCLC patients grouped into ABCP responders and non‐responders. VEGFA was overexpressed in ABCP responders, whereas VEGFC was upregulated in non‐responders. VEGFA and VEGFC had exclusive distributions and interactions, suggesting their distinct roles. VEGFA facilitated the proliferation of responder tumor subcluster cells, whereas VEGFC secreted from non‐responder tumor cells interacted with tumor microenvironment cells. VEGFC predominantly cooperated with drug resistance pathways such as fibroblast growth factor signaling and YAP‐TAZ regulation, whereas VEGFA coordinated several oncogenic signaling pathways. VEGFC expression was the most significant prognostic marker (hazard ratio, 1.8 [95% confidence interval, 1.1–3.0], p = 0.015). Both VEGFA and VEGFC inhibition effectively suppressed tumor growth, suggesting that VEGF signaling complexity hampers the response to ABCP. In conclusion, combinatorial targeting of both ligands (VEGFA and VEGFC) or their receptors (VEGFR2 and KDR) may enhance the clinical benefit of ABCP in EGFR‐TKI‐resistant NSCLC patients.