RET Mutation and Expression in Small-Cell Lung Cancer

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RET Mutation and Expression in Small-Cell Lung Cancer Snehal Dabir, PhD, Shahab Babakoohi, MD, Amy Kluge, BS, James J. Morrow, BS, Adam Kresak, BS, Michael Yang, MD, David MacPherson, PhD, Gary Wildey, PhD, Afshin Dowlati, MD Journal of Thoracic Oncology Volume 9, Issue 9, Pages 1316-1323 (September 2014) DOI: 10.1097/JTO.0000000000000234 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Distribution of primary biopsy samples in small-cell lung cancer diagnosis. The number in parentheses indicates the number of cases. ED, extensive disease; LD, limited disease; PF, pleural fluid; W/B, washing/brushing; FNA, fine needle aspiration. Journal of Thoracic Oncology 2014 9, 1316-1323DOI: (10.1097/JTO.0000000000000234) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Immunohistochemistry (IHC) of RET and p-ERK in tumor no. 22. IHC for RET (left panels) and p-ERK (right panels) are shown for two different areas of the tumor. Images were captured at ×200. Ret positivity was observed in most of the tumor and demonstrated moderate to strong staining of cytoplasm and cell membranes. Phospho-Erk positivity was less consistent than Ret but demonstrated strong nuclear and light cytoplasmic staining when present. The high nuclear content and small cell size characteristic of SCLC are evident. Journal of Thoracic Oncology 2014 9, 1316-1323DOI: (10.1097/JTO.0000000000000234) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Stable RET expression and signaling in small-cell lung cancer cell lines. A, RET expression levels determined by qPCR in parental (Con) versus wild-type (WT) and M918T mutant (Mut) RET overexpressing H1048 and SW1271 cells. Levels were normalized to β-actin. B, Western blot of total RET (150–170 kDa) and MYC expression in parental (C) versus WT and M918T mutant (Mut) RET H1048 and SW1271 cells. β-actin was used as a loading control. C, Western blot of ERK phosphorylation in parental (C) versus WT (W) and M918T mutant (M) RET H1048 and SW1271 cells under basal and GDNF (ng/ml) stimulated conditions (10 minutes) in serum-free medium. A longer exposure of the p-ERK blot (+) is shown to demonstrate increased ERK activation in H1048 cells under basal and 5 ng/ml GDNF conditions. Journal of Thoracic Oncology 2014 9, 1316-1323DOI: (10.1097/JTO.0000000000000234) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Cell growth in stable RET SCLC cells. A, Growth curves in serum-free medium for parental (C) cells versus MUT and wild-type (WT) RET overexpressing H1048 and SW1271 cells. Growth was measured as percent confluence using the IncuCyte ZOOM. B, Cell growth in serum-free medium was measured by the MTT assay after 3 days. C, Dose-response of growth inhibition by vandetanib and ponatinib (in μM) using the MTT assay. Drugs were present for 1 (ponatinib) and 5 (vandetanib) days. All values are normalized to their respective control (no drug). Journal of Thoracic Oncology 2014 9, 1316-1323DOI: (10.1097/JTO.0000000000000234) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 RET expression in lung cancer. A, RET mRNA expression in lung cancer and neuroblastoma cell lines. The line within individual boxes represents the median mRNA expression value of all tested cells, and the circles represent “outlier” cells whose mRNA values do not fall within the 25% to 75% quartile of all mRNA values measured for that subtype (represented by the box). The numbers in parentheses indicate the number of cell lines assayed for RET expression for each subtype. B, Transcript levels of RET, PTEN, and EGFR in a cohort of 15 SCLC tumors reported by Peifer et al.7 Expression was individually normalized to β-actin levels for each tumor. C, Scoring table for RET immunohistochemistry (IHC) in thoracic cancer tissue microarray measured as high (3+), medium (2+), or low (1+) positivity. Count = number of cores analyzed. D, Examples of strong RET IHC staining in neuroblastoma (N), small-cell (SC), adeno- (Ad) and squamous-cell (Sq) lung carcinoma. Images were captured at ×200. Journal of Thoracic Oncology 2014 9, 1316-1323DOI: (10.1097/JTO.0000000000000234) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions