To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.
2 months ago
Preclinical • Journal
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ALK (Anaplastic lymphoma kinase) • AXL (AXL Receptor Tyrosine Kinase)
ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor...However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.
Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed.