Targeting epithelial to mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer
Menée in vitro et in vivo, cette étude suggère l'intérêt du crizotinib pour surmonter une résistance thérapeutique chez les patients atteints d'un cancer du poumon à petites cellules
Purpose: Met receptor phosphorylation is associated with poor prognosis in human SCLC. The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met mediated epithelial mesenchymal transition in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models. Experimental design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (Crizotinib). Human SCLC samples at diagnosis (N:87) and relapse (N:5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and correlated these with patient outcome. Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival and were upregulated in chemorefractory disease. Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and supports clinical trials of Met inhibitors and chemotherapy in this fatal disease.