Therapies targeting specific genetic changes that drive tumour growth can achieve remission with fewer side effects than other less-targeted therapies; however, this approach is hindered by the development of resistance. To identify effective therapeutic combinations that can circumvent resistance, Crystal et al. have developed a screening platform that tests cell cultures grown directly from patient tumour samples against a panel of drugs that target pathways involved in cell growth and survival.
The authors established 20 cell cultures from patients with non-small cell lung cancer whose disease had progressed after treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. Each cell culture was tested against a panel of 76 targeted drugs, both alone and in combination with the first-line drug to which the tumour had become resistant. To confirm the effectiveness of the strategy, the authors also tested the approach in five established cell lines with a known mechanism of resistance developed in vitro. In all five cell lines, the screen accurately identified drugs that effectively targeted the known bypass mechanism of resistance. The approach was then used in a panel of 55 resistant cell lines with unknown mechanisms of resistance, which included the cell cultures established from patient biopsy samples. In these cells, the combination screen included next-generation inhibitors of the gatekeeper mutations (EGFR or ALK) as a primary drug and a second drug. At least one effective combination was identified in 45 of the 55 lines tested. Importantly, treatment with single agents was not effective, emphasizing the importance of developing combination therapies.
This is a preview of subscription content, access via your institution
