DCLK1 regulates tumor stemness and cisplatin resistance in non-small cell lung cancer via ABCD-member-4

Abstract Chemoresistance cells have features similar to cancer stem cells. Elimination of these cells is an effective therapeutic strategy to clinically combat chemoresistance non-small cell lung cancer (NSCLC). Here, we demonstrate that DCLK1 is the key to develop chemoresistance and associated stemness in NSCLC. DCLK1 is highly expressed in human lung adenocarcinoma and strongly correlated with stemness. Silencing DCLK1 inhibits NSCLC cell primary and secondary spheroid formation, which are the prerequisite feature of tumor stem cells. DCLK1 inhibition reduced NSCLC cell migration/invasion in vitro and induce tumor growth inhibition in vivo. NSCLC cells responded differently to cisplatin treatment, indeed the clonogenic ability of all NSCLC cells was reduced. We found that the cisplatin-resistant NSCLC cells gain the expression of DCLK1 compared to their parental control. However, DCLK1 inhibition in cisplatin-resistance NSCLC cells reverses the tumor cell resistance to cisplatin and reduced tumor self-renewal ability. Specifically, we found that DCLK1 mediated cisplatin-resistance in NSCLC is via an ABCD4 dependent mechanism. Our data demonstrate that increased expression of DCLK1 is associated with chemoresistance and enhanced cancer stem cell-like features in NSCLC. Targeting DCLK1 using gene knockdown/knockout strategies alone or in combination with cisplatin may represent a novel therapeutic strategy to treat NSCLC.