Acquired resistance to
tyrosine kinase inhibitors (TKIs) is the major obstacle to improve clinical efficacy in
cancer patients. The epithelial-stromal interaction in tumor microenvironment influences
cancer drug response to TKIs.
Anlotinib is a novel oral multi-targeted TKI, and has recently been proven to be effective and safe for several
tumors. However, if and how the epithelial-stromal interaction in tumor microenvironment affects
anlotinib response in
gastric cancer (GC) is not known. In this study, we found that
anlotinib inhibited GC cells growth by inducing GC cells apoptosis and G2/M phase arrest in a dose- and time-dependent manner.
Reactive oxygen species (ROS) mediated
anlotinib-induced apoptosis in GC cells, while cancer-associated fibroblasts (CAFs) significantly suppressed
anlotinib-induced apoptosis and ROS in GC cells. Increased
BDNF that was derived from CAFs activated TrkB-Nrf2 signaling in GC cells, and reduced GC cells response to
anlotinib. We identified secreted
lactate from GC cells as the key molecule instructing CAFs to produce
BDNF in a NF-κB-dependent manner. Additionally, functional targeting
BDNF-TrkB pathway with
neutralizing antibodies against
BDNF and TrkB increased the sensitivity of GC cells towards
anlotinib in human patient-derived organoid (PDO) model. Taken together, these results characterize a critical role of the epithelial-stroma interaction mediated by the
lactate/
BDNF/TrkB signaling in GC
anlotinib resistance, and provide a novel option to overcome drug resistance.