Dddr-01. p38-mapk inhibitor reversed cisplatin resistance in non-small cell lung cancer brain metastases by regulating p-gp and bcrp of blood-tumor barrier

Abstract BACKGROUND Previous studies have shown that the blood-brain barrier (BBB) of brain metastases (BMs) is destroyed, and the neovascularization and tumor cells constitute the blood-tumor barrier (BTB). Whether the BTB plays a role in the chemotherapy resistance of BMs is lacking in-depth research. This study aims to elucidate the possible role of BTB in cisplatin resistance of BMs from non-small cell lung cancer (NSCLC). METHODS AND MATERIALS; A multicenter retrospective cohort study including 1177 patients with NSCLC-BMs was conducted to explore the prognosis. Immunohistochemistry and immunofluorescence staining were used to verify the expression of some BBB markers in the BTB. Animal models of BMs were constructed by cardiac injection of A549. NSCLC-BMs cell lines A549-mBrain were selected in vivo. Cisplatin susceptibility tests and CCK8 proliferation tests were performed on A549-mBrain. RNA sequencing, Western Blot and qPCR were used to explore the mechanism that might regulate cisplatin resistance in A549-mBrain. RESULTS Platinum-based chemotherapy did not improve the overall survival time of NSCLC-BMs. BTB in NSCLC-BMs lacked astrocytes and pericytes, but still expressed several molecular markers of BBB, such as tight junction, transcytosis, and efflux pump. The efflux pump P-gp and BCRP expressions were higher in NSCLC-BMs than those in the lung primary lesion by immunohistochemistry in patients' tumor section. The A549-mBrain showed cisplatin resistance compared with the parental A549. Besides, the expression of P-gp and BCRP were also higher in A549-mBrain than parental A549 by Western Blot and qPCR. In A549-mBrain, inhibition of the p38-MAPK signaling pathway decreased the expression of P-gp and BCRP, thus increasing the sensitivity to cisplatin. CONCLUSION BTB may retain some BBB function in NSCLC-BMs, in which efflux pump P-gp and BCRP expression were related to cisplatin resistance. p38-MAPK inhibitor reversed cisplatin resistance in NSCLC-BMs by regulating P-gp and BCRP.