Exceptional treatment responses and molecular markers among 103 colorectal cancer cell lines

Vollständiger Abstract

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Abstract Patients with colorectal cancer have few molecularly guided treatment options. Cancers with exceptional treatment response are valuable models for discovery of molecular response mechanisms and might reveal new predictive biomarkers to guide treatment selection. However, the rarity of events is a clinical challenge. We performed integrated high-throughput drug sensitivity testing ( n = 620 drugs) and molecular analyses of 103 colorectal cancer cell lines to build an in vitro foundation for exceptional treatment responses and their molecular markers. Exceptional responses were scored by a two-way outlier detection approach and were identified in 67 unique cell line-drug pairs (0.13% of all pairs tested). This involved 35 cell lines (34.0%) and 49 drugs (7.9%) representing standard, experimental, and non-oncology drugs of diverse classes. Plausible response mechanisms on the gene, protein, and/or pathway expression levels were identified at baseline in 89.6% of the 67 pairs. Experimental validation confirmed treatment-induced marker suppression in seven of eight selected pairs, including target engagement of kinase inhibitors and downregulation of markers of extended response mechanisms. Recurrent exceptional sensitivity to the same drug in different cell lines involved functionally convergent molecular mechanisms, but rarely precisely the same marker. Most exceptional sensitivities (77.8%) could be predicted with multivariable transcriptomic models. In conclusion, this study provides in vitro support for biomarker-guided prescreening to potentially obtain exceptional treatment response to diverse drugs and therapeutic targets in colorectal cancer. Most exceptional responses have a clear molecular underpinning. The study also provides a large and openly available pharmaco-transcriptomics resource for colorectal cancer cell lines.