AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer

In the article (1), Hong et al described a very interesting next generation antisense molecule AZD9150 with early evidence of clinical activity in lymphoma and lung cancer. The findings are very exciting because the data not only confirmed previously published results we and others have generated using very similar to LNA (locked nucleic acid) molecules (2-9) , but also for the first time showed evidence of on target effect in cancer patients, validating this strategy. Like LNA, AZD9150 can penetrate certain cell types and exhibit enhanced in vitro and in vivo potency compared to an unmodified first generation phosphorothioated and other second generation ASOs such as 2’-methoxyethyl ASOs (1). The authors have hypothesized that oligonucleotide uptake pathway may be intact in primary tumors and primary tumor explants while the uptake pathway are lost in vitro when establishing cell lines. However, our data do not necessarily support this hypothesis and more careful studies are needed to address this issue. In support of this proposal, we have shown earlier, even with primary tumor cells (10), that the cellular uptake of LNA-oligonucleotides varies tremendously depending on the tissue origin. Our data with 3 different tumor types and multiple samples for each type have shown that primary cultures derived from one cancer type demonstrated strikingly superior sensitivity to LNA oligonucleotide compared to the other two. We do not think this observation can be simply attributed to different structure and chemistries because Generation 2.5 c-Et oligonucleotide chemistry was developed by substitution with a 4’-carbon in the core bicyclic structure of LNA. Our data suggests that the diverse response to oligonucleotides such as LNA and Generation 2.5 c-Et oligonucleotides can occur in patients and call upon the scientific community to place more efforts to study the mechanism of uptake in order to optimally use these molecules. Moreover, we were able to generate three isogeneic pairs of LNA oligonucleotide resistant cell lines with cross resistance to multiple LNA oligonucleotides. Our data suggested that cells can develop resistance to oligonucleotide drugs due to loss of cellular uptake capability or low target level (10). These observations have important clinical implication as we expect that resistance can develop in patients over time. Lastly, understanding the molecular difference between the isogeneic lines, large cell line panels, and primary tumor cells that show a diverse response to oligonucleotide may provide a strategy to help delineate uptake mechanisms of oligonucleotides, leading to alternative therapies to overcome uptake barrier in certain tumor types and potential resistance.

References
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