Abstract
Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.
Highlights
Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers
For the copy number variations (CNVs) of CDKN2A and CDKN2B in tumor tissue, we found that CDKN2A or CDKN2B loss was detected in 27% (44/161) of the esophageal squamous cell carcinoma (ESCC) samples (Fig. 1b)
The result of ZEC166 (CDKN2A/2B wildtype) was a similar trend to the result of ZEC118 (Supplementary Fig. 5c). These results indicated that ESCC patient-derived cell lines (PDCs) with CDKN2A or CDKN2B loss are sensitive to CDK4/6 inhibitors
Summary
The most frequently mutated genes in the cohort of 161 samples (Fig. 1a) were frequently observed in previous studies of ESCC18–21,23. These included TP53, KMT2D (MLL2), KMT2C (MLL3), NOTCH1, LRP1B, EP300, PIK3CA, FAT1, CREBBP, ADAM29, RB1, NOTCH2, and others (Fig. 1a). Out of 161 ESCCs, 153 (95%) samples have at least one somatic CNV Within these CNVs, eight CNVs have recurrence rates ≥30% (Fig. 1b and Supplementary Data 5). ESCC patients with H3F3A amplification had a significantly shortened DFS (p = 0.003) and a trend of shortened OS (p = 0.160, log-rank test) in comparison to those harboring H3F3A neutral (Supplementary Fig. 2c). To confirm the origin of these PDCs, single-nucleotide polymorphisms (SNP) analysis demonstrated that SNPs in the PDCs were clustered with those in the corresponding tumor tissues (Supplementary Fig. 3c), confirming that the PDCs are derived a DNA sequencing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
