Abstract 1981: MYC downregulation and chemoresistance in non-small cell lung cancer (NSCLC): Evidence from the Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program
Authors: Saintigny Pierre , Byers Lauren A. , Zhang Li , Yordy John S. , Tang Xi M. , Girard Luc , Lang Wenhua , Fan You H. , Ji Lin , Lee Jack J. , Kim Edward S. , Hong Waun K. , Lippman Scott M. , Herbst Roy S. , Minna John , Wistuba Ignacio I. , Heymach John V. , Mao Li 
Published: February 2011

Background: Primary or acquired resistance to platinum-based therapy remains an important issue in the treatment of unresectable non-small cell lung cancer (NSCLC). Our objective was to identify factors of resistance to platinum-based therapy. Experimental procedures: Gene expression profiling from the BATTLE program (pretreated resistant tumors stage III/IV, N=32) and a control group from 2 independent publicly available datasets (never treated tumors stage III/IV, N=45) were compared. Gene expression profiling was generated using the same platform (U133 Plus 2.0 Array). Pathway and gene set analyses were used to define networks and pathways associated with resistance. For validation, we used: i-an independent set of 38 never treated NSCLC stage III/IV, ii-a set of 53 NSCLC cell lines tested for cisplatin sensitivity with proteomic profiling generated by Reverse Phase Protein Array (RPPA) technology using 177 well-characterized antibodies, iii-the comparison of two pairs of NSCLC cell lines (H1437, H460) that were made resistant by iterative exposure to cisplatin, and iv-transfection experiments. Results: A total of 3,963 probesets were found to be differentially expressed between BATTLE samples and the control group with a p-value &lt; 0.001 (two-tailed t-test). DNA repair gene sets were upregulated in BATTLE samples compared to never treated tumors. Network analysis found that MYC as well as many of its downstream regulated genes were significantly downregulated in BATTLE samples. In particular, a high proportion of MYC target genes associated with apoptosis were downregulated. Using real time PCR, MYC gene expression was significantly lower in 15 BATTLE samples compared with an independent set of 38 never treated stage III/IV NSCLC (p-value=0.01). The proteomic profiling of 53 NSCLC cell lines showed that MYC expression was one of the top proteins associated with sensitivity to cisplatin. An inverse correlation was observed between sensitivity to cisplatine (IC50) and MYC protein expression evaluated by RPPA (total MYC: r=-0.41, p-value=0.003; phosphorylated MYC: r=-0.30, p-value=0.03). MYC gene expression by real time PCR was lower in resistant H1437 and H460 cell lines compared to parental cell lines. Finally, transfection of H226 cell lines with a vector expressing MYC improved sensitivity to cisplatin compared to the control. Conclusion: This is the first gene expression profiling analysis of NSCLC samples pretreated and resistant to chemotherapy included in a prospective clinical trial. MYC down regulation may play an important role in NSCLC resistance to platinum-based chemotherapy. Mechanisms of MYC down regulation should be further explored.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1981.