Comprehensive pharmacological profiling in neuroblastoma cell lines using high-throughput microscopy

Chemoresistance is a major impediment to successful treatment of a growing number of cancer entities. This phenomenon can be circumvented through highly selective and efficient drugging of molecular targets and pathways implicated in the chemoresistance phenotype. We have recently discovered that MYC(N)-driven tumors show strong upregulation of genes involved in replicative stress (RS)-induced DNA damage repair (DDR). Thus, exploiting this pathway may offer a novel entry point for combinatorial chemotherapy. However, limited knowledge on drug-gene-phenotype interactions complicates rational selection of promising compounds. To address this topic in a systematic manner, we have established a high-content microscopy-based compound-screening assay that provides a holistic readout on DNA damage response and cell morphology. We have validated the approach using compounds that are known to induce DNA damage or replicative stress in a selected panel of neuroblastoma cell lines with different MYC(N) background. We are now applying it to assess interactions between these compounds and a selected gene set involved in RS/DDR. In doing so, we expect to reveal common modes of action between selected compounds and to infer putative synergies for combinatorial treatments modulating the genes involved in RS and/or DDR. Thus, with our work we aim at devising a more powerful, robust and integrative approach for assessing synthetic lethality. This will be a key strategy for more efficient killing of tumors and for use in patients in which conventional methods no longer show effect