Targeting serine synthesis pathway to reverse paclitaxel resistance in NSCLC with combination of paclitaxel and anlotinib

Abstract Background Paclitaxel (PTX) serves as a first-line chemotherapeutic agent for the treatment of advanced non-small cell lung cancer (NSCLC). However, the emergence of drug resistance poses a significant threat to patient survival. The serine synthetic pathway (SSP) has been implicated in drug resistance across various cancers and is notably activated in NSCLC. Nevertheless, its role in PTX resistance remains poorly understood. Methods In this study, we investigated the influence of the SSP on PTX resistance in NSCLC and explored a novel combination therapeutic strategy involving PTX and anlotinib to reverse NSCLC drug resistance. Specifically, using integrated transcriptomic and metabolomic analyses along with in vitro and in vivo experimental approaches, we aimed to elucidate the regulatory role of activated SSP in PTX resistance and to determine whether the combination of anlotinib and PTX can overcome PTX resistance in NSCLC through modulation of the SSP. Results We found that SSP activation drives PTX resistance by promoting the proliferation of PTX-resistant NSCLC cells, increasing the expression and transport function of P-glycoprotein (P-gp), inducing epithelial-to-mesenchymal transition (EMT), and maintaining redox homeostasis. Anlotinib synergizes with PTX by suppressing SSP. This leads to attenuated glycolysis, disruption of the AKT/ERK proliferative signaling pathway, inhibition of P-gp expression and function, reversal of EMT, and redox imbalance, which subsequently elevates reactive oxygen species (ROS) levels and activates the mitochondrial apoptosis pathway, ultimately inducing apoptosis. Conclusion Collectively, our study demonstrates that anlotinib combined with PTX, via SSP inhibition, is a promising strategy for overcoming PTX resistance in NSCLC. Graphical abstract The combination of anlotinib and PTX effectively suppresses the SSP in A549/PTX cells. This suppression results in the following effects: (1) disruption of AKT/ERK proliferation signaling pathway transmission; (2) inhibition of P-gp expression and its efflux function; (3) blockade of the EMT process; (4) activation of the mitochondrial apoptosis pathway, thereby inducing cell apoptosis. Furthermore, the inhibition of SSP also exerts a certain degree of suppression on the glycolytic activity of A549/PTX cells.