Abstract 3010: Osteosarcoma cell lines display both shared and unique vulnerabilities to 140 targeted small molecules with RNA-seq revealing putative mechanisms
Authors: Kahen Elliot J. , Welch Darcy , Teer Jamie , Brohl Andrew S. , Yoder Sean J. , Zhang Yonghong , Cen Ling , Reed Damon 
Published: August 2019

BACKGROUND: Osteosarcoma is the most common bone sarcoma in children, adolescents, and young adults. Osteosarcoma primarily arises through tumor suppressor inactivation, most typically due to TP53 attenuation mechanisms. Increasingly additional oncogenic and tumor suppressor pathways are being recognized in subsets of osteosarcoma. We hypothesized that novel insights into mechanisms of sensitivity and resistance for emerging targeted therapies could be elucidated by combining activity and genomic information across cell line models of osteosarcoma.

METHODS: In this study we evaluated 6 established osteosarcoma cell lines (U2-OS, MG-63, OS252, SAOS-2, 143B, MNNG) representing several TP53 and other tumor suppressor inactivation mechanisms with human osteoblasts as a control. We have obtained RNA-seq profiles detailing genomic variants, gene fusions, and expression of both protein-coding and miRNA genes for these cell lines. In addition to genomic changes, we evaluated 140 chemical probes and candidate drug molecules across these cell lines.

RESULTS: RNAseq identified TP53 changes in 5 of 6 cell lines with OS252, SAOS2 and MG-63 having intron 1 translocations and 143B and MNNG sharing a TP53 gain-of-function mutation. Variant calling from the whole exome sequencing data revealed additional putatively oncogenic mutations. Additionally, we observed differential gene expression patterns compared to control samples in genes associated with genomic stability, epigenetic regulation, and transcriptional activity. Differential sensitivities to several classes of small molecules were seen across the cell lines and were associated with genomic changes that warrant additional investigation such as: RAD51 pathway genomic findings associated with sensitivity to RS-1, disulfuram activity varying according to aldehyde dehydrogenase activity, and variable response to inhibitors of ATR and specific CDKs that are associated with the expression of their respective targets. Additional pathways of interest that demonstrate differential response to small molecules include histone/protein deacetylation, telomerase activity, protein translation, and others. Unique vulnerabilities associated with tumor suppressor or oncogenic changes specific to an individual cell line will be presented.

CONCLUSIONS: By characterizing response to small molecules in the context of gene expression, underlying pathway vulnerabilities may be determined for further testing suggesting potential biomarkers for basket trials. Other agents with shared sensitivities to agents across cell lines may be translated in a different manner.

Citation Format: Elliot J. Kahen, Darcy Welch, Jamie Teer, Andrew S. Brohl, Sean J. Yoder, Yonghong Zhang, Ling Cen, Damon Reed. Osteosarcoma cell lines display both shared and unique vulnerabilities to 140 targeted small molecules with RNA-seq revealing putative mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3010.