P3.02c-004 SBI0206965, a Novel Inhibitor of Ulk1, Suppresses Non-Small Cell Lung Cancer Cell Growth via Modulating Both Autophagy and Apoptosis Pathways: Topic: Targeted Therapy

Abstract

Autophagy is a catabolic process that regulates the lysosomal turnover of damaged proteins and organelles in order to maintain cellular homeostasis. Dysregulation of autophagy is often observed in lung cancer. Kinase inhibitors have proved successful in the clinic. The fact that uncoordinated (Unc) 51-like kinase (Ulk1) is the only conserved serine/threonine kinase in the autophagy cascade makes it a very attractive target for therapeutic development. Up-regulation of Ulk1 has been shown to promote cell survival of several cancer cell lines. Moreover, overexpression of Ulk1 has been shown to be negatively correlated with the prognosis of several types of human cancer. However, the role of Ulk1 in NSCLC is largely unknown. We evaluated Ulk1 expression levels in human normal lung epithelial cell line BEAS-2B and five NSCLC cell lines, A549, H460, H1299, H292 and HCC827. We analyzed the correlation between Ulk1 expression levels and the prognosis of NSCLC patients. We evaluated the effect of SBI0206965 alone or in combination with cisplatin on cell proliferation, apoptosis and autophagy in two human NSCLC cell lines, A549 and H460. Cell proliferation of untreated or drug-treated cells was measured by CCK8 assay. Percentage of apoptotic cells was measured using PE-conjugated Annexin V with a flow cytometer. Autophagy was determined by conversion of LC3I to LC3II and p62 degradation using Western blot. Ulk1 is overexpressed in NSCLC cell lines and negatively correlated with the prognosis of NSCLC patients. The inhibition of Ulk1 by a selective inhibitor, SBI0206965, blocks the proliferation of NSCLC cells and induces apoptosis. SBI0206965 treatment augments the efficacy of cisplatin to kill NSCLC cells by inhibiting cisplatin induced cell protective autophagy. SBI0206965 can also destabilize Bcl2/Bclxl to promote cisplatin induced apoptosis in NSCLC cell lines. Our results suggest that the inhibition of Ulk1 may be a promising strategy for the treatment of NSCLC. SBI0206965 may be a promising agent for the treatment of NSCLC by modulating autophagy and apoptosis pathways. Furthermore, the combination of SBI0206965 with classical chemotherapy agents represents a promising therapeutic strategy that warrants further clinical evaluation in NSCLC.