Furthermore, the involvement of LMTK3 in invasion ( 12), migration ( 12), chromatin remodeling ( 13), and microRNA biogenesis ( 6) in BC has also been documented.
While high LMTK3 mRNA expression has been reported to be an independent poor prognostic factor in patients with ERα + BC ( 17), immunohistochemistry (IHC) analysis has further revealed that tumors overexpressing human epidermal growth factor receptor 2 (HER2) are more likely to be LMTK3 positive, while triple-negative BC (TNBC) tumors have high cytoplasmic expression of LMTK3 ( 8). Follow-up studies have demonstrated that LMTK3 is overexpressed in more aggressive forms of BC, and it is implicated in endocrine ( 9) and chemotherapy resistance ( 10) in BC. LMTK3 has been originally identified via a kinome screening as a regulator of estrogen receptor α (ERα) in breast cancer (BC) ( 5), able to protect it from ubiquitin-mediated proteasomal degradation. The oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been established over the past years, supported by mechanistic and translational data in different tumor types and settings in vitro and in vivo ( 5– 16). Our data reinforce LMTK3 as a druggable target for cancer therapy. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28).
Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Chayen, Heinz-Josef Lenz, John Spencer, Chrisostomos Prodromou, Apostolos Klinakis, Justin Stebbing, and Georgios Giamas Show FewerĮlucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Nettleship, … Show All …, Jae Ho Lo, Shivani Soni, Goar Smbatyan, Panagiota Ntavelou, Teresa Gagliano, Maria Chiara Iachini, Sahir Khurshid, Thomas Simon, Lihong Zhou, Storm Hassell-Hart, Philip Carter, Laurence H. Angeliki Ditsiou, Chiara Cilibrasi, Nikiana Simigdala, Athanasios Papakyriakou, Leanne Milton-Harris, Viviana Vella, Joanne E.