ALK-EML4-Positive Cancers and Combination Therapy: Probing the Apoptotic Threshold

Undergraduate Honors Thesis

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/w66344171

Abstract

Of all diseases currently being researched, lung cancer is one of the most pressing due to its worldwide prevalence and high incidence of fatality. More specifically, non-small cell lung cancers (NSCLC) harboring ALK-EML4 gene fusion mutations are of particular interest to researchers due to their widely documented capability of becoming resistant to specialized treatment, such as kinase inhibition. This project was initiated with the aim of using in vitro combination drug treatment to more efficaciously inhibit the growth and survival of H3122 cells, an ALK-EML4-positive NSCLC cell line. In this study, H3122 cells were subjected to combined ALK and histone deacetylase (HDAC) inhibition; two ALK inhibitors, crizotinib and AP23116, were combined with paragazole, a class-1 HDAC inhibitor. Both combinations, crizotinib/paragazole and AP23116/paragazole, were found to produce lower EC₅₀ values than single-drug treatment. While each drug pair confers synergistic activity, the latter combination was found to be substantially more potent. ALK and HDAC inhibition in combination proves to be an effective means of treating ALK-EML4-positive cells and could be a successful approach to counteracting acquired drug resistance in cancers with ALK rearrangements.

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