Abstract PR10: Exploiting the G2-M cell cycle checkpoint dependency in small cell lung cancer (SCLC) using pharmacological inhibitors of CHK1 and WEE1

In this study we investigated the effect of CHK1 (LY2606368) and WEE1 (AZD1775) inhibitors as therapeutic targets for SCLC.Methods: Protein and gene expression was determined by immunoblot and real-time-RT-PCR respectively. Effect of the drugs on cell viability was determined by CellTiter-Glo. Efficacy of LY2606368 in H69 (chemosensitive) and H69/CR (chemoresistant) models was further determined by in vivo flank tumor regression analysis. The effect of LY2606368 monotherapy was also tested in a spontaneous SCLC genetically engineered mouse model (GEMM) model. The mechanistic studies were conducted by immunoblot analysis, apoptosis assay and flow cytometry. Pre and post-treatment cell lysates were analyzed by reverse phase protein array (RPPA) for biomarker exploration.Result: Higher expression of CHK1 and WEE1 was observed in SCLC patient tumor samples compared to normal lung (p<0.001) and in SCLC cells as compared to NSCLC cells (p<0.05). LY2606368 showed efficacy in both primary and acquired cisplatin resistant in vitro and in vivo models. LY2606368 treatment showed striking single agent activity in a spontaneous GEMM model of SCLC. Proteomic analysis identified an association between LY2606368 sensitivity and high levels of the CMYC protein. The level of CMYC decreased upon LY2606368 treatment (p<0.001) while pro-apoptotic pathways increased (p<0.05). CHK1 was a top marker of cisplatin sensitivity and treatment of cells with LY2606368 reduced activation of the ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Managing G2/M Control: Oral Presentations - Proffered Abstracts Source Type: research