Abstract LB-170: Unique microRNA signatures in small cell lung cancer correlate with distinct protein expression profiles and drug response
Authors: Gay Carl M. , Kundu Samrat , Diao Lixia , Glisson Bonnie S. , Wang Jing , Heymach John V. , Byers Lauren A. , Gibbons Don L. 
Published: July 2016

Abstract
In the decades since the introduction of platinum-etoposide, treatment of small cell lung cancer (SCLC) remains virtually unchanged. Data from our lab and others have identified novel targets now being investigated in clinical trials. However, further characterization of the molecular heterogeneity within SCLCs will be critical to identify subsets with specific therapeutic vulnerabilities and change the treatment paradigm, similar to what has occurred in non-small cell lung cancer (NSCLC). Here we report expression analyses of 2578 microRNAs (miRs) in 62 SCLC cell lines, followed by unsupervised clustering to identify three distinct miR subtypes. Using ANOVA, we then identified differences in mRNA and protein expression (by reverse phase protein array), as well as drug response, which corresponded to miR expression profiles. The first subtype is characterized by low expression of miR-200, a family with known function in epithelial to mesenchymal transition (EMT) and previously implicated in cisplatin resistance. miR-200 low lines have significantly higher EMT scores (using our published EMT signature), as well as increased sensitivity to the polo-like kinase 1 (PLK-1) inhibitor GW843682X (p = 0.007), the sensitivity to which is associated with EMT in NSCLC. In addition, this subtype possesses increased expression of c-MYC (p = 1.03 e-05), a known repressor of miR-200. A second miR subtype is defined by reduced expression of miR-378, a family whose expression predicts cisplatin sensitivity in NSCLC. This subtype is also typified by increased expression of Wee1 (p = 5.91 e-04), a putative target in SCLC, as well as increased sensitivity to inhibitors of protein phosphatase 1D (PPM1D), tropomyosin receptor kinase A (TrkA) and B-Raf (p = 0.009, 0.011 and 0.032, respectively). The third subtype is distinguished by reduction in several miRs including miRs-216 and -217, a family with a putative role as tumor suppressors in pancreatic adenocarcinoma. Intriguingly, this subtype shows an increase in multiple proteins associated with immune checkpoint pathways, such as programmed death ligand 1 (PDL-1), cluster of differentiation 40 (CD40) and MHC class I polypeptide-related sequence A (MICA) (p = 6.38 e-04, 0.016 and 0.039, respectively) suggesting a group that may have enhanced response to immune-checkpoint inhibition. These subtypes are divided almost equally among the tested lines, constituting 34%, 32% and 34%, respectively. This is the first report of SCLC heterogeneity at the miR level and provides preliminary evidence regarding differences in mRNA and protein expression, as well as drug sensitivity between SCLC with distinct miR profiles. Integrated analysis across miRs, mRNA, protein and drug response represents a powerful tool for identifying candidate biomarkers for drug response, novel molecular targets and insights into the biological heterogeneity across SCLC.
Citation Format: Carl M. Gay, Samrat Kundu, Lixia Diao, Bonnie S. Glisson, Jing Wang, John V. Heymach, Lauren A. Byers, Don L. Gibbons. Unique microRNA signatures in small cell lung cancer correlate with distinct protein expression profiles and drug response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-170.