Targeted therapies that disrupt oncogenic signalling pathways are associated with high response rates in populations of patients with tumours harbouring sensitizing mutations; however, the degree of tumour regression and the duration of clinical responses are limited, and development of drug resistance and cancer progression is uniformly observed. Now, a preclinical study by Anna Obenauf et al. has disclosed the secrets of resistance to tyrosine kinase inhibitors (TKIs). These new insights have clinical implications, revealing rational combination therapies that might avert or at least delay resistance.
“The rapid emergence of clinical drug resistance might be facilitated by a small number of pre-existing cancer cells that are intrinsically resistant or poised to quickly adapt to drug treatment,” explains Obenauf. Thus, in vitro and in vivo models of heterogeneous tumour cell populations, in which a small population of resistant tumour cells was present at the start of therapy, were developed. “The first step was to establish cell lines resistant to targeted therapy by exposing the drug-sensitive parental population to kinase inhibitors in vitro.” Obenauf continues, “after several weeks, we retrieved cells that were resistant to higher doses of the drug and transduced them with a construct expressing green fluorescent protein and luciferase, allowing us to track growth and metastasis of the resistant tumour-cell population in a variety of animal models using bioluminescent imaging.” Tumour heterogeneity was modelled by injecting these labelled, treatment-resistant cells with an excess of unlabelled, drug-sensitive cells, at proportions of 0.05% and 99.95%, respectively.
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