PLK1 Inhibitor Exerts Strong Antitumor Activity And Reverses Chemotherapy Resistance In Small Cell Lung Cancer

Small-cell lung cancer(SCLC)is a neuroendocrine tumor which accounts for 15-20% of all lung cancer cases.It is a malignancy that exhibits rapid tumor growth and early development of widespread metastases,which means the prognosis of SCLC patients is very poor.About two-thirds of patients have extrathoracic metastases at the time of diagnosis,and the five-year overall survival rate is only 5-7%.Although SCLC patients respond favorably to the first-line chemotherapy,most patients die within two years because of the recurrence and metastases.In addition,most of the recurrent SCLC patients are resistant to cisplatin therapy,and the therapeutic effect of second-line treatment is unsatisfactory.Therefore,it is urgently needed to explore more effective treatment strategies for SCLC and recurrent SCLC patients.Polo-like kinase 1(PLK1)is a highly conserved serine/threonine protein kinase.It regulates several mitotic events and participates in DNA damage response and the repair processes.In recent years,the overexpression of PLK1 has been found in numerous tumor types,and studies found that PLK1 played a crucial role in oncogenesis and development of tumors.Moreover,the expression level of PLK1 is related to the tumor malignancy,higher PLK1 expression correlates with tumor aggressiveness and a poor prognosis,which means PLK1 could be an attractive therapeutic target for the treatment of tumors.BI 6727(volasertib)is a small-molecule inhibitor of PLK1 with high potency and selectivity,which inhibits the kinase activity of PLK1 by competitively binding to the ATP binding domain.In several preclinical and clinical studies,BI 6727 shows encouraging antitumor activity as a monotherapy or as part of PLK1 inhibitor-based combination treatments in various cancers.However,the efficacy and mechanisms of PLK1 inhibition in SCLC are still unclear.Our study focused on the research of anti-tumor efficacy of PLK1 inhibitor BI 6727 in SCLC and recurrent SCLC,and figuring out the underlying mechanisms.First of all,the expression of PLK1 in SCLC was detected by IHC and its correlation with clinicopathological features was analyzed.The effect of BI 6727 on proliferation,cell cycle,apoptosis and DNA damage were detected by CCK-8,flow cytometry,comet assay and western blot.Then,we detected the efficiency of BI 6727 in vivo.Meanwhile,the role of PLK1 in cisplatin-resistant SCLC and mechanisms of BI 6727 in reversing cisplatin resistance were further discussed.In this study,we found the PLK1 protein was expressed at higher level in SCLC,while was hardly expressed in normal lung tissue,and the expression of PLK1 was related to clinical stage and prognosis of patients.PLK1 inhibitor BI 6727 significantly inhibited the proliferation of SCLC cells,while the proliferation of normal bronchial epithelial cells was barely affected.In vitro,BI 6727 induced G2/M arrest and DNA damage through the ATR/ATM-Chk1/Chk2 pathway,and led to apoptosis in a caspase-3-dependent mitochondrial pathway.Moreover,BI 6727 significantly inhibited the growth of xenograft and induced DNA damage and apoptosis in vivo.In addition,we found the expression of PLK1 was increased in cisplatin-resistant SCLC cells,and the knock-down of PLK1 could partially reverse the resistance to cisplatin.BI 6727 treatment significantly inhibited the proliferation and induced DNA damage in cisplatin-resistant cells,and reduced the expression of Rad51,a DNA damage repair protein.Furthermore,it induced apoptosis of cisplatin-resistant cells.In conclusion,PLK1 plays a crucial role in the development of SCLC and its resistant to chemotherapy,our findings indicate that PLK1 maybe a potential therapeutic target for SCLC patients.